Muscular Dystrophy - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

MUSCULAR DYSTROPHY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES J...

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MUSCULAR DYSTROPHY A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Muscular Dystrophy: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83659-0 1. Muscular Dystrophy-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on muscular dystrophy. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON MUSCULAR DYSTROPHY .......................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Muscular Dystrophy..................................................................... 4 E-Journals: PubMed Central ..................................................................................................... 106 The National Library of Medicine: PubMed .............................................................................. 109 CHAPTER 2. NUTRITION AND MUSCULAR DYSTROPHY ............................................................... 245 Overview.................................................................................................................................... 245 Finding Nutrition Studies on Muscular Dystrophy ................................................................. 245 Federal Resources on Nutrition ................................................................................................. 250 Additional Web Resources ......................................................................................................... 251 CHAPTER 3. ALTERNATIVE MEDICINE AND MUSCULAR DYSTROPHY ........................................ 253 Overview.................................................................................................................................... 253 National Center for Complementary and Alternative Medicine................................................ 253 Additional Web Resources ......................................................................................................... 260 General References ..................................................................................................................... 262 CHAPTER 4. DISSERTATIONS ON MUSCULAR DYSTROPHY .......................................................... 263 Overview.................................................................................................................................... 263 Dissertations on Muscular Dystrophy ...................................................................................... 263 Keeping Current ........................................................................................................................ 266 CHAPTER 5. CLINICAL TRIALS AND MUSCULAR DYSTROPHY ..................................................... 267 Overview.................................................................................................................................... 267 Recent Trials on Muscular Dystrophy ...................................................................................... 267 Keeping Current on Clinical Trials ........................................................................................... 272 CHAPTER 6. PATENTS ON MUSCULAR DYSTROPHY ..................................................................... 275 Overview.................................................................................................................................... 275 Patents on Muscular Dystrophy................................................................................................ 275 Patent Applications on Muscular Dystrophy............................................................................ 290 Keeping Current ........................................................................................................................ 298 CHAPTER 7. BOOKS ON MUSCULAR DYSTROPHY ......................................................................... 299 Overview.................................................................................................................................... 299 Book Summaries: Federal Agencies............................................................................................ 299 Book Summaries: Online Booksellers......................................................................................... 300 The National Library of Medicine Book Index ........................................................................... 304 Chapters on Muscular Dystrophy ............................................................................................. 305 CHAPTER 8. MULTIMEDIA ON MUSCULAR DYSTROPHY .............................................................. 309 Overview.................................................................................................................................... 309 Bibliography: Multimedia on Muscular Dystrophy .................................................................. 309 CHAPTER 9. PERIODICALS AND NEWS ON MUSCULAR DYSTROPHY ........................................... 311 Overview.................................................................................................................................... 311 News Services and Press Releases.............................................................................................. 311 Academic Periodicals covering Muscular Dystrophy................................................................ 317 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 321 Overview.................................................................................................................................... 321 NIH Guidelines.......................................................................................................................... 321 NIH Databases........................................................................................................................... 323 Other Commercial Databases..................................................................................................... 325 The Genome Project and Muscular Dystrophy ......................................................................... 325 APPENDIX B. PATIENT RESOURCES ............................................................................................... 333 Overview.................................................................................................................................... 333

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Patient Guideline Sources.......................................................................................................... 333 Associations and Muscular Dystrophy...................................................................................... 339 Finding Associations.................................................................................................................. 347 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 349 Overview.................................................................................................................................... 349 Preparation................................................................................................................................. 349 Finding a Local Medical Library................................................................................................ 349 Medical Libraries in the U.S. and Canada ................................................................................. 349 ONLINE GLOSSARIES................................................................................................................ 355 Online Dictionary Directories ................................................................................................... 358 MUSCULAR DYSTROPHY DICTIONARY ............................................................................. 359 INDEX .............................................................................................................................................. 439

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with muscular dystrophy is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about muscular dystrophy, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to muscular dystrophy, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on muscular dystrophy. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to muscular dystrophy, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on muscular dystrophy. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON MUSCULAR DYSTROPHY Overview In this chapter, we will show you how to locate peer-reviewed references and studies on muscular dystrophy.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and muscular dystrophy, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “muscular dystrophy” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Effects of Myotonic Dystrophy and Duchenne Muscular Dystrophy on the Orofacial Muscles and Dentofacial Morphology Source: Acta Odontologica Scandanavica. 56(6): 369-374. December 1998. Summary: This article reviews two of the less rare myopathies: myotonic dystrophy (MyD) and Duchenne muscular dystrophy (DMD), and their effect on the orofacial muscles and dentofacial morphology. A high prevalence of malocclusions was found among the patients affected by these diseases. The development of the malocclusions in MyD patients seems to be strongly related to the vertical aberration of their craniofacial growth due to the involvement of the masticatory muscles in association with the possibly less affected suprahyoid musculature. Thus, a new situation is established around the teeth transversely. The lowered tongue is not in a position to counterbalance

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the forces developed during the lowering of the mandible by the stretched facial musculature. This may affect the teeth transversely, decreasing the width of the palate and causing posterior crossbite. The lowered position of the mandible, in combination with the decreased biting forces, may permit an overeruption of the posterior teeth, with increased palatal vault height and development of anterior open bite. The development of the malocclusions in DMD patients also seems to be strongly related to the involvement of the orofacial muscles by the disease. However, the posterior crossbite is not developed owing to the narrow maxillary (upper jaw) arch, as is the case in MyD patients. On the contrary, the posterior crossbite in DMD is due to the transversal expansion of the mandibular arch, possibly because of the decreased tonus of the masseter muscle near the molars, in combination with the enlarged hypotonic tongue and the predominance of the less affected orbicularis oris muscle. 2 figures. 33 references.

Federally Funded Research on Muscular Dystrophy The U.S. Government supports a variety of research studies relating to muscular dystrophy. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to muscular dystrophy. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore muscular dystrophy. The following is typical of the type of information found when searching the CRISP database for muscular dystrophy: •

Project Title: 2002 GORDON RESEARCH CONF. ON INTERMEDIATE FILAMENTS Principal Investigator & Institution: Coulombe, Pierre A. Professor; Biological Chemistry; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2002; Project Start 30-JUN-2002; Project End 31-DEC-2002 Summary: (provided by applicant): The purpose of this application is to generate funds to support travel, registration, and lodging for participants in the 7th Gordon Research Conference on Intermediate Filaments, which will be held June 30th-July 5th 2002 at Roger Williams University in Bristol, Rhode Island. Intermediate filaments (IFs) are prominent components of the cytoskeleton and nuclecoskeleton in higher eukaryotes. In the public draft of the human genome, there are greater than 67 functional genes encoding IF-forming polypeptides. These genes are typically regulated in a cell typespecific manner and highly conserved in mammalian genomes. A general function of IF polymers is to endow cells and tissues with the mechanical resilience they need to withstand various types of physical and non-physical stresses. Defects in IF proteins

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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underlie a vast number of genetically determined fragility disorders involving epithelia (e.g., skin, oral, and eye blistering diseases; inflammatory bowel diseases; liver disorders), muscle (e.g., cardiomyopathies; muscular dystrophy), neural tissue (e.g., amyotrophic lateral sclerosis; Alexander's diseases), and even adipose tissue (e.g., lipodystrophy). IFs fulfill other functions in a differentiation and context-dependent fashion, including promoting specific cytoarchitecture, tissue response to injury and other forms of stress, response to apoptotic signals, signaling, and nuclear architecture and gene expression (lamins). This Gordon Research Conference (GRC) is said to represent the only regular meeting devoted to IF biology. It brings together participants of junior and senior rank from all over the world who are studying IFs from a wide variety of angles. This GRC has traditionally fostered a free-flowing exchange of novel ideas, tools, and reagents, and facilitated the establishment of productive collaborations. The Program for the 2002 edition of the Conference has been finalized. The following major themes will be covered: 1) Atomic structure of IFs: From models to reality; 2) Regulating IF assembly and dynamics in vivo; 3) IFs and cell and tissue mechanics; 4) IF-associated cytolinkers: Mechanical integration and other functions; 4) Function of IFs in C. elegans, in muscle and neurons; 5) Functions of keratins in epithelia: Beyond scaffolding?; and 6) Laminopathies, lamin functions, and the nuclear envelope. In addition, there will be a special "Perspectives" session and a platform session dedicated to the discussion of posters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: A RESOURCE FOR MAGNETIC RESONANCE AND OPTICAL RESEARCH Principal Investigator & Institution: Leigh, John S. Professor of Radiology; Radiology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 30-SEP-1984; Project End 31-AUG-2004 Summary: The regional resource develops innovate magnetic resonance (MR) and optical technologies for biomedical research. These technologies are driven by both basic and clinical research collaborators in the biomedical field to address specific clinical problems and to further fundamental understanding of biophysical, structural, and functional properties of biological systems in vivo. In conjunction with its collaborators, the resource has developed four broad areas of core research. The first core deals with the use of multinuclear MR techniques to study the structural and metabolic properties of cartilage, brain, and muscle, with direct application to osteoarthritis, stroke, and muscular dystrophy. This core also investigates the use of multinuclear MR to monitor the efficacy of gene therapy in the setting of muscle disease. In the second core, the resource presents developments and improvements in quantitative perfusion and diffusion imaging, in comparison to PET. The third core deals with innovative techniques for quantitative structural imaging of multiple organ systems. These techniques include MR of hyperpolarized gases, novel contrast generation using zeroquantum coherences, and imaging of tissue microstructure. The fourth core focuses on combining optical and MR imaging techniques for the study of neurophysiology, peripheral vascular disease, and breast cancer. Technology developed by these cores will drive sixteen collaborative projects in the study of various normal and pathological tissues. Services provided by the resources include access to the 2 Tesla research magnet, coil-building facility, in- magnet exercise devices, and computer software developed by the resource. The resource also maintains an active training program consisting of seminars, MR courses, workshops, training lectures, practical training in MR and optical methods, and disseminates its research through news letters,

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presentations at national and international conferences, and a resource web site that provides access to all publications and software packages developed by the resource. The research resource remains committed to intellectual interchange and the interdisciplinary pursuit of basic and clinical medicine. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACQUISITION SPECTROMETER

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Principal Investigator & Institution: Wysocki, Vicki H. Professor; Chemistry; University of Arizona P O Box 3308 Tucson, AZ 857223308 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2004 Summary: (provided by applicant): This proposal requests a Thermo Finnigan ProteomeX DECAP-51000 Integrated Workstation, an ion trap mass spectrometer equipped with LC pumps, a 10 port switching valve, strong cation and reversed phase columns for multidimensional chromatography, and a nanospray probe. This instrument will serve the needs of a number of University of Arizona bioscience researchers. The major users and their applications for the instrumentation are (1) Samuel Ward, Molecular and Cellular Biology, Study of signaling pathways during cell differentiation in the Nematode C.elegans, genes are homologeous to human disease genes linked to Alzheimer's and muscular dystrophy; (2) Brian Larkins, Plant Sciences, College of Agriculture and Life Sciences, Identificationand Analysis of Proteins Required for Improved Maize Protein Nutritional Quality; (3) M. Halonen/D. Vercelli/F. Martinez/M. Cusanovich, Center for Respiratory Sciences, Transcription Factors that Bind Regulatory Elements in the Immunoglobulin G4 Germline Promoter, the IL-13 Promoter, and the CD 14 Promoter; Cellular and Molecular Mechanisms of Asthma (4) Elizabeth Vierling, Molecular and Cellular Biology, Molecular chaperone function; expression and function of cytoplasmic organelle and heat shock proteins, the pathways studied are critical to normal cell function; (5) Carol Dieckmann, Biochemistry, Identification of Mutations in Genes Coding for Major Polypeptides in the Chlamydomonas Eyespot; (6) Thomas Baldwin, Biochemistry, Pulsed Alkylation MS to Investigate Protein Folding in Bacterial Luciferase; (7) Vicki Wysocki, Chemistry, Mechanisms and Energetics of Peptide Dissociation, this work is directly applicable to the identification of proteins from biological organisms. Modern protein research cannot be accomplished without mass spectrometry. The access to a dedicated microflow LCmass spectrometer with a nanospray probe to characterize samples that are not amenable to analysis with the current mass spectrometry facility instruments is critical to the maximum productivity and success of these projects. The University has made a strong commitment to the project by by renovating space for a new "branch" mass spectrometry laboratory that is located in Biosciences, by hiring a full time Ph.D. biological mass spectrometry specialist (about $60,000 per year), by providing funds for a Director of Proteomics (about $80,000/year) and a technician (about $35,000/year) to help with sample preparation, and by providing cost sharing in the amount of $75,000. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACTININ ASSOCIATED LIM PROTEIN & FSH MUSCULAR DYSTROPHY Principal Investigator & Institution: Bredt, David S. Professor; Physiology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-FEB-1996; Project End 31-JAN-2003

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Summary: Disruptions of the myofiber cytoskeleton underlie several genetic muscular dystrophies, including Duchenne and Limb-girdle muscular dystrophies. In addition to these dystrophin-related disorders, certain inherited muscular dystrophies are due to mutations in cytoskeletal proteins that do not interact with the dystrophin complex. Identification of the responsible proteins and clarification of mechanisms that regulate the myofiber cytoskeleton are therefore critical goals. Recent molecular cloning studies have identified actinin-associated LIM protein (ALP), which is a novel component of the muscle cytoskeleton. ALP contains a PDZ protein motif that is also present in certain dystrophin-associated proteins, yet ALP does not interact with dystrophin. Instead ALP binds to actinin, a structural homologue of dystrophin, and ALP associates with actinin at the Z-lines of skeletal muscle. Chromosomal mapping studies show that ALP occurs in 4q35, within 7 Mb of the telomeric region that is deleted in facioscapulohumeral muscular dystrophy (FSHD), the most common autosomal muscular dystrophy. ALP is the only muscle-specific gene yet found to map in this region. Therefore, a possible role for ALP in the pathogenesis of FSHD must be explored. We now propose to characterize the molecular interaction of ALP with actinin and to determine the composition and function of the ALP-associated complex at the Z-lines. To help assess whether ALP participates in FSHD, we will determine whether ALP expression is altered in muscle biopsies from diseased patients. Because FSHD is a dominant disease, it is likely that only one allele of the responsible gene(s) will be abnormal. To address this, we will also evaluate allele-specific expression of ALP in FSHD muscle samples. Because complex genetics underlie FSHD, studies of human tissues alone may not decisively identify the responsible gene(s). We will therefore target disruption of ALP in stem cells and breed mice that lack ALP protein. Muscle development, histology and function will be carefully evaluated in the ALP mutants. Assembly of the ALP-associated protein complex at the Z-lines will also be evaluated in the mutants. If these mutant mice manifest signs that resemble FSHD this would implicate a role for ALP in this disease and the mice would provide a unique animal model. The proposed studies will lead to a better understanding of formation and function of the myofiber cytoskeleton and may provide insight in the pathogenesis and treatment of FSHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ADENO-ASSOCIATED VIRUS (AAV) VECTORS TO IMPROVE MATURE MUSCLE FUNCTION Principal Investigator & Institution: Xiao, Xiao; Associate Professor; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 01-APR-2001; Project End 31-MAR-2002 Summary: Muscular dystrophies are a relatively common group of inherited degenerative muscle disease. Most types are caused by mutations in genes coding for membrance associated proteins in muscle. Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy (LGMD) often manifest themselves in young ages and lead to early morbidity with no currently available effective treatment. These diseases are recessive, loss-of- function of the corresponding gene product, which makes them suitable for gene replacement therapy. Recombinant adeno-associate virus (rAAV) is one promising gene replacement vector based on defective human parvoviruses. The rAAV system has attracted attention due to its non- pathogenicity, genomic integration, transduction of quiescent cells, and apparent lack of cellular immune reactions. In contrast to other viral vectors, rAAV is capable of efficiently bypassing the myofiber basal lamina and transducing mature muscle cells. We have demonstrated that rAAV vectors harboring a foreign gene can achieve highly efficient and sustained gene

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expression in mature muscle of immunocompetent animals for more than 1.5 years without detectable toxicity. Recently, significant improvement in vector production methodology has made it possible to generate high titer and high quality rAAV vectors completely free of helper adenovirus contamination. However, no experiments using rAAV vectors to restore the functional deficits in muscle tissue itself have been reported to date. Here, we propose to take advantage of rAAV vector system, to test two therapeutic genes (delta-sarcoglycan and a highly truncated dystrophin), under the control of two different promoter systems (viral/CMV or muscle- specific/MCK), in two relevant animal models of muscular dystrophies (Bio14.6 hamster for LGMD and mdx mouse for DMD). Two distinct vector delivery methods, local intramuscular infection versus systemic delivery will be utilized. We have the following three hypotheses to be tested. 1): muscle deficient in delta-sarcoglycan can be functionally rescued by genetic complementation using intramuscular AAV vector injection in the LGMD hamster model. 2) systemic delivery of the delta-sarcoglycan gene can be mediated by rAAV vectors through intra-artery or intra-ventricle injection. 3) a dystrophin mini-gene lacking the central rod domain will improve the function of dystrophin-deficient muscle when delivered into dystrophic mdx mice by AAV vectors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS AND MODULATION OF IMMUNITY IN GENE THERAPY Principal Investigator & Institution: Clemens, Paula R. Associate Professor; Neurology; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001; Project Start 01-JAN-1999; Project End 31-DEC-2003 Summary: (Abstract): Therapeutic gene transfer is a logical approach to the treatment of inherited genetic deficiency diseases, many of which have no other adequate treatment. However, persistent expression of the therapeutic gene in the target tissue and/or the capability of repeat administration will be required. To date, adenoviral (Ad) vectormediated gene transfer trials have resulted in an immune response that eliminates the therapeutic protein. This immunity may be due either to the expression of the therapeutic protein itself, to Ad proteins or both. The future success of human gene therapy trials using the Ad vector as a vehicle will likely depend on a comprehensive understanding of this immune response and novel strategies to modulate it. Although the therapeutic protein to be provided by a gene therapy vector is a self-protein in healthy individuals, the patients who would be treated by gene transfer lack this selfprotein due to a germ-line mutation (a null mutant). Examples include Factor IX deficiency, cystic fibrosis and Duchenne's muscular dystrophy (DMD). DMD provides an excellent model with which to study gene transfer treatment for an inherited protein deficiency because the mutant gene and defective protein are known, the target tissue is easily accessible and the mdx mouse strain, which models human DMD, is readily available. The investigators recently have described the development and use of a novel high-capacity Ad vector that has all viral genes removed and can accommodate 30 kb of insert DNA. This vector is the most promising to date for decreasing the immunity induced by therapeutic Ad vectormediated gene delivery; no AD antigens are expressed from the vector, and the use of a muscle-specific promoter should reduce antigen presentation by professional antigen presenting cells. The five aims of this application will lead to the characterization and modulation of the immune response induced by therapeutic gene delivery to skeletal muscle. The first group (Aims 1, 2 and 3) will analyze the immune response to specific antigens. The second group (Aims 4 and 5) has as a common thread the modification of vector characteristics to improve high-

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capacity Ad vector-mediated gene delivery to muscle by modulating the immune response to the antigens studies in Aims 1-3. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF ASKS, COMPONENTS OF SCF UBIQUITIN-LIGASES Principal Investigator & Institution: Gingerich, Derek J. Horticulture; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2006 Summary: (provided by applicant): The majority of targeted protein degradation in the cell is performed by the ubiquitin (Ub)/26S proteasome pathway, which is highly conserved in all eukaryotic species. In this pathway, proteins to be degraded are covalently tagged with multiple ubiquitins, which serves as the degradation signal, by the sequential action of three enzymes. The final enzyme in this process, the E3 Ubligase, binds the target and catalyzes attachment of the Ub moiety to the protein. This proteolytic pathway has been shown to be important for a wide range of cellular processes, including cell cycle progression, DNA repair, hormone signal transduction and receptor regulation, and degradation of abnormal proteins. It also has been implicated genetically in a number of diseases, including cancer, Parkinson's disease, and muscular dystrophy, arguing for the need to study this pathway in more detail. One subfamily of E3 Ub-ligases is the SCF (Skpl, Cullin/Cdc53, F-box protein) complex. In Arabidopsis thaliana 19 genes encode Skpl homologues and 694 genes encode F-box proteins. Presumable the 19 ASKs combine with the 694 F-box proteins to generate a hierarchy of SCF complexes capable of labeling a wide range of targets. I propose a line of research that studies the functions of the ASK genes in Arabidopsis. By using genetic, biochemical, and cytological approaches to characterize the function of ASKs, I hope to better understand the roles that SCF complexes play in various cellular processes in Arabidopsis. The remarkable conservation of the Ub/26S proteasome pathway means these studies should contribute to our understanding of its function in all eukaryotes, which could lead to new strategies to affect the pathway for medicinal or agricultural benefit. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALYSIS OF DELTA-SARCOGLYCAN IN CARDIOMYOPATHY Principal Investigator & Institution: Allikian, Michael J. Medicine; University of Chicago 5801 S Ellis Ave Chicago, IL 60637 Timing: Fiscal Year 2001; Project Start 15-SEP-2001 Summary: Mutations in the dystrophin-associated proteins, gamma- and deltasarcoglycan, have been shown to cause both cardiomyopathy and muscular dystrophy in humans. It has recently been shown that dominant negative mutations in deltasarcoglycan can cause dilated cardiomyopathy in humans. This is in contrast to the null mutations that have previously been shown to produce muscle and heart degeneration in humans and mice. Delta-sarcoglycan is a 35 kD type II transmembrane protein. Delta sarcoglycan is expressed in heart, skeletal and smooth muscle and forms an integral part of the sarcoglycan complex. We plan to study these dominant negative mutations in cell culture as well as transgenic mice in order to ascertain their effects on other components of the dystrophin glycoprotein complex including dystrophin, laminin, filamin and nitric oxide synthase. We are proposing to study heterozygous mutations in deltasarcoglycan because these mutations likely result in disrupted interactions within the j dystrophin-glycoprotein complex. Therefore, we will gain an increased understanding

10 Muscular Dystrophy

of the etiology of dilated cardiomyopathy through the investigation of deltasarcoglycan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ANALYSIS OF THE MOLECULAR AND FUNCTIONAL ROLE OF D4Z4 Principal Investigator & Institution: Tupler, Rossella G. Research Assistant Professor; Biochem and Molecular Biology; Univ of Massachusetts Med Sch Worcester Office of Research Funding Worcester, MA 01655 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary neuromuscular disorder of unknown cause, characterized by an insidious onset and progressive course. It has been causally related to deletions of tandemly arrayed 3.3 kb repeat units (D4Z4) on chromosome 4q35 possibly affecting expression of nearby genes by a process analogous to position effect variegation (PEV). Interestingly, we observed over-expression of 4q35 genes in FSHD muscles. We discovered that HMG2, a non-histone nuclear protein involved in heterochromatin formation, is specifically associated to a 27 bp element within D4Z4. We demonstrated that HMG-2 mediates gene silencing at 4q35 and its removal increases gene expression levels, explaining the observed over-expression of those genes in FSHD dystrophic muscles. Our experiments suggest that D4Z4 maintains 4q35 silencing by interacting with a transcriptional repressive complex. It is thus plausible that reduction of repeat number to a critical threshold might induce the over-expression of proximal genes and trigger FSHD pathogenesis. The long term of our studies is to elucidate the FSHD pathogenic process through the analysis of the molecular events occurring at D4Z4. To this aim we will characterize the D4Z4 repressing complex through biochemical purification and functional analysis. We will investigate the effects of D4Z4 deletion on 4q35 gene expression in normal and affected muscle tissues. We expect this analysis to provide a number of genes specifically deregulated in FSHD. Subsequently we will analyze the biological functions of candidate genes in appropriate model organisms. Silencing at 4q35 might also be hampered by abnormalities of repressing complex proteins. Therefore it is possible that non-4q35 FSHD cases might be related to mutations of genes coding those proteins. To this aim, we will screen for mutations in candidate genes all the myopathic individuals referred us for FSHD in which no D4Z4 deletions were detected. Our studies will provide relevant information to understand the molecular basis of FSHD and to develop effective therapeutic strategies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ANALYSIS OF TORSIN PROTEIN FUNCTION IN C. ELEGANS Principal Investigator & Institution: Caldwell, Guy A. Biological Sciences; University of Alabama in Tuscaloosa Tuscaloosa, AL 35487 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2006 Summary: (provided by applicant): Dystonia is estimated to be six times more prevalent than Huntington's Disease, ALS, or Muscular Dystrophy. However, as few as 5% of the over 350,000 persons in North America estimated to be affected have been correctly diagnosed and are under treatment (NIH Budget Office). The most severe early-onset form of this disorder has been linked to a mutation in a human gene named TOR1A that encodes torsinA, a protein that is also localized to inclusions in the brains of Parkinson's patients termed Lewy bodies. While a causative genetic mutation has been identified,

Studies 11

the cellular mechanisms of pathogenesis underlying dystonia remain unknown. We are applying the advantages of the model organism, Caenorhabditis elegans, towards a detailed analysis of two specific torsin-related gene products in this nematode. The chromosomal positioning of these genes suggests that they may represent a functionally co-expressed unit and preliminary studies from our laboratory indicate they act neuronally. Phylogenetic analysis of the torsin family indicates these proteins share distant sequence similarity with the functionally diverse AAA+ family of proteins. We have determined that ectopic overexpression of a C. elegans torsin homolog results in a reduction of polyglutamine repeat-induced protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression quantitatively persisted as animals aged. Antibody staining of transgenic animals using antisera specific to TOR-2 indicated this protein was highly localized to sites of protein aggregation. We propose to extend these preliminary studies through a combination of reverse genetic approaches designed to investigate the cellular role of torsin proteins in the nematode. The specific aims of the proposed project include: 1) to determine what phenotypes are associated with C. elegans torsin homologues; 2) to define sites of C. elegans torsin protein function; and 3) to determine potential effectors of torsin activity. These studies will further our understanding of the molecular mechanisms responsible for early-onset torsion dystonia. Moreover, the aberrant protein deposition associated with diverse neurodegenerative disorders like Parkinson's Disease and those caused by polyglutamine expansion such as Huntington's Disease warrants further investigation of any putative neuroprotective effects of torsins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASTROCYTE DEVELOPMENT

DYSTROGLYCAN

COMPLEXES

IN

BRAIN

Principal Investigator & Institution: Moore, Steven A. Professor; Pathology; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001; Project Start 20-APR-2001; Project End 31-MAR-2004 Summary: (Applicant's abstract): The dystrophin-glycoprotein complex (DGC) is a well characterized array of cytoplasmic, membrane spanning, and extracellular matrix proteins that form a critical linkage between the cytoskeleton and the basal lamina of striated muscle. Within the central nervous system (CNS), similar dystroglycan linkages to basal laminae are present at two interfaces formed by astrocytes: (1) foot processes abutting on cerebral blood vessels and (2) foot processes that form the glia limitans at the pial surface of the brain. The former interface is critical for formation and maintenance of the blood-brain barrier, while the latter is likely to play important roles in anchoring radial glia during neuronal migration. Basal lamina abnormalities at the glia limitans have been identified in some forms of congenital muscular dystrophy in humans (e.g. Fukuyama muscular dystrophy) and basal lamina disruption at the glia limitans leads to abnormal CNS development in animal models. In this proposal, we will focus attention on the central protein in the astrocyte-basal lamina linkage, dystroglycan. Our Specific Aims propose to identify protein elements of the astrocytedystroglycan complex, elucidate protein interactions within the complex, and demonstrate the importance of the astrocyte dystroglycan complex during CNS development. Through the use of Cre-lox methodology, we plan to create a novel murine model of CNS developmental disorders. This project is a cross-discipline collaboration among investigators with expertise in clinical neuropathology and in basic neuroscience, molecular biology, cell biology, and membrane physiology who are uniquely situated to carry out the proposed studies. Aim 1: To define the composition of


the astrocyte-dystroglycan complex(es), we will test the hypothesis that one-or-more dystroglycan complexes are present in astrocytes using a combination of biochemical and immunohistochemical methods. These studies will utilize tissue sections and cultured astrocytes from wild type mice and mice with naturally occurring or genetically engineered mutations of one or more of the DGC components known to be expressed in astrocytes. Aim 2: To create a new model of CNS developmental abnormalities by selectively disrupting the astrocyte-dystroglycan complex. Dystroglycan +/-, dystroglycan lox/lox, and GFAP-Cre mice will be bred to produce GFAP-Cre/dystroglycan lox/- and GFAP-Cre/dystroglycan lox/lox mice. This strategy should disrupt the astrocyte DGC beginning in the latter half of embryonic development. We believe this strategy will produce mice with neuronal migration and cerebrovascular defects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIGLYCAN AS A THERAPEUTIC FOR MUSCULAR DYSTROPHY Principal Investigator & Institution: Mcquillan, David J.; Lifecell Corporation 1 Millenium Way Somerville, NJ 08876 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 14-MAR-2003 Summary: (provided by applicant): The overall goal of this proposal is to use animal models to test the efficacy of biglycan as a protein therapeutic for muscular dystrophy. Duchenne's muscular dystrophy (DMD) is a heritable disease that affects approximately 1 in 3,500 boys. These children are usually wheelchair-bound by age 12 and rarely survive past their early twenties. There are currently no effective treatments for the underlying pathology of DM0. The molecular pathogenesis of Duchenne's and many other muscular dystrophies has been traced to a specialized ensemble of proteins at the muscle cell surface known as the dystrophin-associated protein complex (DAPC). Mutation of dystrophin leads to disruption in the organization of the DAPC. The resulting failure of DAPC function results in muscle cell damage and loss. We have recently discovered that the extracellular matrix molecule biglycan is expressed at the muscle cell surface and binds, by distinct mechanisms, to the ectodomains of three core constituents of the DAPC: alpha-dystroglycan, aipha-sarcoglycan and gammasarcoglycan. These molecular interactions indicate that biglycan can bridge the component subcomplexes of the DAPC and thus coordinate and stabilize the entire complex from outside the cell. Indeed, biglycan null (bgn-/o) mice display a dystrophic phenotype as evidenced by weakened muscle cell membranes and cell death. These observations suggest that biglycan could serve as a therapeutic to stabilize the DAPC from its extracellular aspect when dystrophin is absent. Biglycan thus represents a new path for developing therapies for muscular dystrophies. Importantly, since the biglycan-DAPC interactions are wholly extracellular, biglycan can be introduced to the muscle by systemic delivery of the purified recombinant protein. This program will utilize unique production methods to produce sufficient quantities of high quality biglycan,.and test efficacy in several animal models of muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DYSTROPHY

BIOENGINEERING

RESEARCH

PARTNERSHIP--MUSCULAR

Principal Investigator & Institution: Sweeney, H. Lee. Professor and Chairman; Physiology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2001; Project Start 20-SEP-2000; Project End 31-AUG-2005

Studies 13

Summary: (Applicant's abstract verbatim) The goal of this BRP is to utilize a number of aspects of bioengineering in order to develop tools and therapeutics for the treatment and monitoring of muscular dystrophies. The project is collaboration between three investigators and includes the following areas of bioengineering relevant to the PA: 1) cell and tissue engineering, 2) imaging and 3) therapeutics. Collectively we will delineate factors that when expressed in muscle may slow that rate of degeneration that is concomitant with either the complete (Duchenne muscular dystrophy) or partial (Becker muscular dystrophy) loss of dystrophin. These studies will utilize the mdx mouse as the animal model for dystrophin deficiency. The long-term goal is to gain the understanding and tools necessary to develop adeno-associated (AAV)-based gene therapy for Duchenne and Becker muscular dystrophies. Three parallel lines of investigation (each directed by one of the three investigators) are proposed: Section 1: a dissection the mechanical role of dystrophin and muscle adhesion proteins (directed by Dennis Discher); Section 2: an assessment of the functional benefits of restoring adhesion molecules to dystrophic muscle using recombinant adeno-associated virus gene delivery (directed by H. Lee Sweeney, Ph.D.); and Section 3: development of non-invasive methods for monitoring therapeutic benefits of dystrophin gene transfer (directed by Glenn Walter, Ph.D.). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CAVEOLIN-3 AND MUSCULAR DYSTROPHY Principal Investigator & Institution: Lisanti, Michael P. Molecular Pharmacology; Yeshiva University 500 W 185Th St New York, NY 10033 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: The long-term objective of this proposal is to understand the role of muscle caveolae and caveolin-3 i) in normal muscle development; and ii) in the pathogenesis of muscle dystrophy. Caveolae are "little caves" at the surface of cells. It has been proposed that caveolae function as message centers" for regulating signal transduction. Caveolin3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cell types (cardiac and skeletal). Recently, we identified a novel autosomal dominant form of limb girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human caveolin-3 gene (3p25). The aim of this proposal is to test the hypothesis that caveolin-3 expression is important for normal muscle development and that changes in caveolin-3 expression (either up-regulation or down-regulation) can result in muscular dystrophy phenotype. In order to test this hypothesis, we will use a variety of complementary in vivo approaches, such as the use of caveolin-3 anti-senses in cultured cells and the development of mouse animal models. The specific aims of the project are: 1) To determine the role of caveolin-3 mutations in the pathogenesis of LGMD- 1C. We will examine the phenotypic behavior of LGMD-1C mutations of caveolin-3 after heterologous expression in NIH 3T3 cells, as compared with wild-type caveolin-3; 2) To develop transgenic mouse models that over wild-type caveolin-3 and LGMD-1C mutant forms of caveolin-3. We will over-express wild type and LGMD-1C mutant forms of caveolin- 3 as transgenes in mice and assess their effects on skeletal muscle. As caveolin3 levels are up-regulated in Duchenne's muscular dystrophy, these experiments will help us evaluate if caveolin-3 up-regulation contributes to the pathogenesis of this diseases; and 3) To examine if caveolin-3 expression is required for normal muscle development. Using an anti-sense approach, we will abrogate caveolin-3 expression in C2C12 cells, a skeletal myoblast cell line that differentiates in culture. We will then assess the effects of caveolin-3 down-regulation on C2C12 myoblast fusion and myotube


formation. In addition, through a targeted gene disruption approach, we will create and characterize "knock-out" mice that lack caveolin-3 gene expression. It is expected that these studies will contribute fundamen6tal knowledge toward understanding the role of muscle cell caveolae in normal muscle development and muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR SIGNALING AND MUSCULAR DYSTROPHIES Principal Investigator & Institution: Rando, Thomas A. Assistant Professor; Neurology & Neurological Scis; Stanford University Stanford, CA 94305 Timing: Fiscal Year 2001; Project Start 15-AUG-2001; Project End 14-AUG-2006 Summary: The muscular dystrophies are devastating diseases of progressive weakness due to apoptotic and necrotic death of muscle cells. The normal cellular mechanisms regulating cell survival that are disrupted in these diseases are not well understood. Several forms of muscular dystrophy are due to abnormalities of membrane proteins and protein complexes, such as integrins and caveolins, that are known to regulate cellular signaling pathways in general, and cell survival signaling in particular, in different cell types. Others, such as those due to dystrophin mutations, are due to abnormalities of protein complexes that are postulated to transduce signals from the extracellular matrix into the cell. We will focus on three proteins/protein complexes that cause muscular dystrophies when a component of the complex is deficient or defective alpha5beta1 integrin, caveolin-3, and the dystrophin-glycoprotein complex (DGC). The experiments of this proposal are designed to explore the cellular signaling processes the promote cell survival via these membrane protein complexes, and the mechanisms of cell death when these complexes are disrupted. For studies of integrin signaling, we will use cells genetically deficient in alpha5 integrin to test which isoforms of protein kinase C are important in alpha5 integrin mediated muscle cell survival (based on our previous finding of the importance of protein kinase C in this process). We will explore how alpha5 integrin deficiency leads to muscle cell death by testing for dysregulation of cell survival/cell death pathways involving the Bcl family of proteins, cytochrome c release from mitochondria, and activation of the caspase cascade. We will also examine the role of activation of the PI3 kinase/Akt pathway in alpha5 integrin- mediated muscle cell survival. For studies of the DGC, we will investigate how disruption (genetically, by antibody inhibition, or by antisense expression) of the association of the complex with the extracellular matrix may lead to cell death. In these studies, we will also examine cells for dysregulation of cell survival mechanisms involving Bcl family proteins since apoptosis has been shown to be the earliest change in muscle associated with dystrophin deficiency. For studies of dystrophies due to caveolin-3 mutations, we will render muscle cells functionally deficient in caveolin-3 using both antisense methods and dominant negative inhibitors. We will study the mechanisms by which caveolin-3 deficiency lead to muscle cell death, and we will test whether these mechanisms involve the disruption of either normal integrin signaling or signaling through the DGC. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHARACTERIZATION OF MYOSTATIN AND GDF-11 Principal Investigator & Institution: Lee, Se-Jin; Associate Professor; Molecular Biology and Genetics; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 08-DEC-1997; Project End 30-NOV-2007 Summary: (provided by applicant): Myostatin (MSTN) and GDF-11 are secreted proteins that we originally identified in a screen for novel growth and differentiation

Studies 15

factors related to transforming growth factor-Beta (TGF-B). The predicted sequences of MSTN and GDF-11 are greater than 90% identical in the mature, C-terminal portion of the proteins, and together, these molecules form their own subgroup within the larger TGF-B superfamily. We have been using a variety of in vitro and in vivo approaches, including gene targeting in mice, to attempt to identify the biological functions of MSTN and GDF-11. We have shown that mice lacking MSTN have dramatic and widespread increases in skeletal muscle mass, suggesting that MSTN normally functions as a negative regulator of muscle growth. We have also shown that mice lacking GDF-11 have extensive homeotic transformations of the axial skeleton, suggesting that GDF-11 normally acts as a global regulator of axial patterning. The overall aim of this proposal is to further investigate the biological functions of these molecules and the mechanisms by which their activities are regulated. The specific aims are: to investigate the functional redundancy of MSTN and GDF-11; to analyze the effect of postnatal loss of MSTN and GDF-11 on skeletal muscle mass; to further characterize the role of activin type II receptors in regulating MSTN and GDF-11 signaling; to identify other components of the MSTN and GDF-11 receptor complex; to further investigate the role of follistatin in regulating MSTN and GDF-11 activity; and to investigate the mechanism by which latent MSTN is activated. Taken together, these studies will provide important insights into the normal biological functions of these molecules and may suggest new strategies for modulating the activities of these molecules for human therapeutic applications in muscle wasting diseases, such as muscular dystrophy and cachexia, andmetabolic diseases, such as obesity and type II diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLINICAL AND MOLECULAR ANALYSIS OF OREGON EYE DISEASE Principal Investigator & Institution: Pillers, De-Ann M. Associate Professor; Pediatrics; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2001; Project Start 30-SEP-1994; Project End 31-MAY-2003 Summary: (Verbatim from applicant's abstract): The title of the application is "Clinical and molecular analysis of Oregon Eye Disease." A more current title would be "Dystrophin and the retina." During the initial application period, it was shown that dystrophin, the product of the Duchenne muscular dystrophy (DMD) gene, is involved in retinal electrophysiology. Three lines of evidence support this. The position of a mutation in the DMD gene predicts the ERG phenotype, and abnormal ERGs were correlated in large part with mutations of a specific isoform of dystrophin, Dp260, which was identified and cloned from retina. New data suggests that other muscular dystrophies are associated with defects in retinal electrophysiology. Specifically, mouse models with defects in laminin-2 have abnormal ERGs. Dystrophin is part of a cellular continuum from the actin cytoskeleton to laminin and the extracellular matrix via a transmembrane group of proteins known as dystrophin-associated glycoproteins (DGC). It is hypothesized that defects in the interaction between retina-specific isoforms of dystrophin and the DGC result in altered retinal electrophysiology and an abnormal ERG. It is proposed that the retinal isoform Dp260 plays an important role in retinal electrophysiology by interfacing with the DGC at the photoreceptor to bipolar synapse. It is further proposed that dystrophin isoforms with non-overlapping cellular distributions have distinct roles in retinal function. Three specific aims will be performed to test these hypotheses, involving: (1) defining genotype-phenotype correlations for the DGC performing ERGs on both mutant mice and patients with defects in these proteins; (2) defining the specific cell synapse responsible for the ERG


abnormalities demonstrated in the mdxCV3 mouse by in vitro cell-specific electrophysiology; and (3) delineating the diversity of dystrophin isoform expression in retina and to determining unique aspects of isoform structure and expression that may contribute to retinal electrophysiology. The long-term goals are to delineate the pathway by which dystrophin contributes to the normal ERG. By so doing, proteins will be identified, which when mutated, will be candidate genes for inherited retinal disorders associated with abnormal electrophysiology. Dystrophin and other proteins including members of the DGC will be targets for future gene therapy approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONING AND CHARACTERIZATION OF GENES EXPRESSED IN SKIN Principal Investigator & Institution: Uitto, Juoni J. Professor and Chair; Thomas Jefferson University Office of Research Administration Philadelphia, PA 191075587 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: (provided by applicant): The overall goal of this project continues to be the elucidation of gene/protein systems for novel components of the cutaneous basement membrane zone and the epidermis. This goal is based on the premise that previously uncharacterized proteins are apparently present in the skin, and such proteins could potentially serve as candidate gene/protein systems in different heritable disorders affecting the skin. Thus, information on these new proteins and the corresponding genes is fundamental to comprehensive study of mutations in these diseases. During the past four years of support, we have made major progress in this project. Specifically, we have characterized a number of basement membrane zone genes, and the cDNA and gene probes developed in this project have been instrumental in molecular characterization of mutations in various forms of EB as well as in other disorders affecting the epidermis. An example of such gene/protein systems is the plectin/HD-1, for which we have determined the entire primary sequence by cDNA cloning, we have determined the intron-exon organization of the corresponding gene, and we have performed its chromosomal assignment (1). Furthermore, based on this sequence information we have developed mutation detection strategies, both by heteroduplex scanning and protein truncation tests, which have been successful in identifying a large number of mutations in a specific variant of EB associated with late-onset muscular dystrophy (EB-MD) (2-6). Furthermore, we have identified and characterized several novel genes expressed in the epidermis, including ladinin, a novel BMZ component (7), periplakin, an epidermal envelope protein(8,9), and desmo-15, a desmosomal autoantigen in pemphigus herpetiformis recognized by circulating IgG antibodies in the patients? sera (10). Some of these genes were initially isolated by immunoscreening of cDNA libraries with antibodies from patients with acquired autoimmune blistering diseases. Furthermore, we have identified novel protein-protein interactions by the yeast two-hybrid genetic screen employing a number of BMZ protein domains as baits (see Progress Report). Finally, we have cloned a number of selected mouse cDNA and genomic sequences which have been helpful in development of animal models for EB. An example is cloning of the mouse type VII collagen genomic sequences which were used to construct a "knock-out" vector resulting in the development of a mouse line mimicking human recessive dystrophic EB with extensive blistering phenotype (11, 12). In continuation of this project, we will concentrate our efforts towards completing current studies on three novel epidermal gene/protein systems, viz. ladinin, periplakin, and desmo-15. Secondly, we plan to identify additional novel, previously uncharacterized gene sequences by utilizing immunoscreening methodologies with autoantibodies in patients

Studies 17

with acquired forms of blistering skin diseases. Furthermore, we plan to explore the BMZ supramolecular organization by identification and characterization of novel genes which encode interactive proteins, as detected by the yeast-two hybrid genetic screen. Finally, we plan to clone selected mouse cDNA and genomic sequences so as to allow development of animal models for human epidermal diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLONING/CHARACTERIZATING A MYOTONIC DYSTROPHY LOCUS Principal Investigator & Institution: Ranum, Laura P. Associate Professor; Neurology; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, MN 554552070 Timing: Fiscal Year 2001; Project Start 01-JUN-1997; Project End 31-MAY-2005 Summary: Myotonic dystrophy (DM) is a multisystem disease and the most common form of muscular dystrophy in adults. In 1992, one form of DM was shown to be caused by an expanded CTG repeat in the 3' untranslated region of the myotonin protein kinase gene (DMPK) on chromosome 19. Although multiple theories attempt to explain how the CTG expansion causes the broad spectrum of clinical features in DM, there is no consensus about how this mutation, which does not alter the protein coding region of a gene, affects cellular function. We have identified a five-generation family (MN1) with a genetically distinct form of myotonic dystrophy. Affected members have the characteristic features of DM (myotonia, proximal and distal limb weakness, frontal balding, cataracts, and cardiac arrhythmias) but do not have the chromosome 19 mutation. We have mapped the disease locus (DM2) for the MN1 family to a small region of chromosome 3 (Nature Genetics 19:196- 198). This proposal outlines a strategy to identify and characterize the DM2 locus. Understanding what is common to chromosome 19 DM (now designated DM1 by the DM consortium) and DM2 at the molecular level should shed light on the mechanisms responsible for the broad constellation of clinical features present in both diseases. Our specific aims are: 1) to develop a high-resolution map of the DM2 region (0.5-1.0 cM) using haplotype and linkage disequilibrium analysis of 29 DM2/PROMM families from Minnesota and Germany; 2) to identify the expressed genes and repeat motifs in the region and prioritize candidates based on homology and expression patterns; 3) to identify the DM2 mutation; 4) to characterize the DM2 gene and investigate whether or not the pathogenic molecular changes found in DM2 are part of a common pathway also affected in DM1; 5) to determine whether molecular changes affecting RNA splicing, CUG binding proteins, and apamin receptors are similar to those found in DM1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COGNITIVE GENETIC ASPECTS OF DUCHENNE MUSCULAR DYSTROPHY Principal Investigator & Institution: Hinton, Veronica J. Gertrude H Sergievsky Center; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2003; Project Start 01-MAY-1996; Project End 30-JUN-2007 Summary: (provided by investigator): The objective of this study is to investigate neuropsychological function in individuals diagnosed with Duchenne muscular dystrophy (DMD) as a model for developmental neuroscience. DMD is a single-gene disorder that interferes with the expression of the protein dystrophin and its isoforms. The consequences of lack of dystrophin in muscle are well known; boys have progressive muscular weakness that results in death generally by their third decade of


life. Dystrophin isoforms are also missing from the central nervous system, yet what functional consequences that may have is unclear. Interdisciplinary study of the cognitive profile, the behavioral attributes, and the molecular genetics of DMD will examine genotype/phenotype associations. The study will build on work that ascertained neuropsychological function in a group of 136 boys diagnosed with DMD and was completed during the tenure of an R29 award. Those data confirmed that boys with DMD who are of average intelligence have selective deficits in verbal working memory with intact declarative memory and visuospatial skills, poor social skills and delayed language developmental milestones. Selected subjects from the established cohort will be examined more thoroughly in focused paradigms to tease apart their language and short-term memory skills using a battery of tests designed to examine the hypothetical "phonological loop." Additionally, subjects will be tested on measures of social function and awareness. New subjects will also be enrolled to increase our sample size for genetic analyses. Subjects with more mild manifestations of the disorder (boys with Becker's muscular dystrophy and carrier females) will be tested on neuropsychological measures to determine whether they present with cognitive phenotypes. An ongoing longitudinal study of a sample of 26 boys will be continued with neuropsychological testing every other year. And newly characterized preschool boys with DMD will be followed to track their language and emotional development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COLLOQUIUM ON THE CYTOSKELETON AND HUMAN DISEASE Principal Investigator & Institution: Wilson, Leslie; Professor; Biological Sciences; University of California Santa Barbara 3227 Cheadle Hall Santa Barbara, CA 93106 Timing: Fiscal Year 2001; Project Start 11-APR-2001; Project End 10-APR-2002 Summary: (provided by applicant): A broadly focused international research meeting on the cytoskeleton and its associated proteins in human diseases is planned from April 17 through April 20, 2001. The meeting, entitled Colloquium on the Cytoskeleton and Human Disease, will be held on the medical/pharmacy school campus of the University of the Mediterranean, specifically at the Faculte de Pharmacie, which is located in the center of Marseille. We expect approximately 150 participants including graduate students and post doctoral fellows. It has become clear that the major cytoskeletal components, microtubules, intermediate filaments, and actin filaments, are involved in a large number of diverse human diseases. Thus our purpose is to assemble scientists to participate in the first broadly-based research meeting on the cytoskeleton and its associated proteins in human disease. New drugs and new targets related to the cytoskeleton and its associated proteins will be highlighted. The meeting will consist of invited lectures, short oral communications, and poster sessions. Topics to be covered include: 1)microtubules and cancer (microtubule-targeted anticancer drugs, drug resistance, new approaches and new compounds), 2)microtubule-associated proteins and neurodegenerative disease (Alzheimer's disease and other tauopathies, new concepts and new targets), 3)intermediate filaments and disease (keratin and skin diseases, desmin in skeletal and cardiac muscle disease, muscular dystrophy), and 4)microfilaments and disease ()cell adhesion, migration metastasis, infectious diseases, membrane muscle defects, potential new targets). The members of the organizing committee from the United States are Drs. Leslie Wilson, Mary Ann Jordan, Ernest Braguer, Vincent Peyrot, and Bernard Rossignol. Drs. Wilson, Briand, Jordan, Hamel, Marvaldi, and Binder have the primary responsibility for the scientific program, and Drs. Briand, Wilson, Briand, Wilson, Braguer, Peyrot, and Rossignol are in charge of meeting arrangements.

Studies 19

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COMPUTATIONAL ANALYSIS OF HUMAN 'AT-RISK' DNA MOTIFS Principal Investigator & Institution: Stenger, Judith E. Assistant Professor; Medicine; Duke University Durham, NC 27706 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2005 Summary: (Taken from the Candidate's Abstract) At-Risk DNA Motifs (ARMS), which include repetitive elements such as Alu sequences, homonucleotide runs and triplet repeats, are potentially unstable segments of the human genome. ARMS are a factor in genetic susceptibility to disease, requiring particular combinations of genetic backgrounds and environmental triggers to express a disease phenotype. While some of the mechanisms are understood, it is not clear under what circumstances repetitive DNA elements mediate pathological mutagenesis. Although a high burden of these sequences is generally tolerated in humans, they can have an enormous impact on health by contributing to diseases that have devastating effects on afflicted individuals. For example, Alus have been linked to numerous diseases including Fanconi anemia, alphazerothalassemia, leukemia, hypertension, neurofibromatosis, breast, and colon cancers. Trinucleotide repeat expansions have been linked with Kennedy's Disease, Huntington's Disease, myotonic muscular dystrophy, and Friedreich ataxia. The long term objective of this proposal is to gain insight into the genetic factors that mitigate gene rearrangement in hopes of predicting when the presence of a repetitive element truly constitutes a threat to the health of an individual. The hypothesis is that the characterization of ARMS according to all possible attributes (i.e. size of repeats, separation distances between repeats, orientation, sequence similarity between repeats, nucleotide base constitution and proximity and/or containment of mutagenic and/or toxicological agent targets, DNA processive or other enzymatic target sites) can reveal largely excluded situations that can be viewed as unstable. It is also postulated that a multidimensional database of repetitive sequences characterized according to the aforementioned attributes can be used to predict repetitive elements that are most prone to mutation, ARMS, while increasing our understanding of the interactions between these genetic elements and their environment. The approach is to use a combination of computational biology and molecular genomic analysis to locate and analyze ARMS. The specific aims of this proposal are to: 1) characterize available data according to the conceivable relevant attributes of size, distance, orientation, degree of homology, base constitution and containment of known target sequences. 2) To test the hypothesis by computationally identifying loci that have already known to contain ARMS linked to a mutation resulting in disease, and then to identify specific genes that may be at-risk for mutation and experimentally testing them using molecular biological approaches. 3) To set up an interactive on-line database and program server so that the scientific community can use the information and apply it to drive experimental research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CONFERENCE--CALPAIN GENE FAMILY IN HEALTH AND DISEASE Principal Investigator & Institution: Mellgren, Ronald L. Professor; Federation of Amer Soc for Exper Bio Bethesda, MD 208143998 Timing: Fiscal Year 2001; Project Start 01-JUN-2001; Project End 31-MAY-2002


Summary: Support is requested for a FASEB Summer Research Conference on "Calpain Gene Family in Health and Disease" to be held June 30 through July 5, 2001 at The Big Mountain resort in Whitefish, Montana. The calpains are regulated intracellular proteases which participate in a variety of signal transduction pathways, are involved in cytoskeletal remodeling in physiologic and pathophysiologic conditions, and appear to participate in some apoptotic pathways. Several of the calpain family members require the intracellular second messenger Ca2+ for activity. The conference is meant to foster exchange of ideas and collaborations between the many diverse laboratories studying calpains. Participants will include many pioneering calpain researchers as well as young investigators who have recently begun research in this area. Topics will include: 1) Structure/function relationships of the calpains, including likely contributions on calpain crystal structure in the presence of Ca2+, or associated with the natural inhibitor protein, calpastatin. 2) Novel calpain gene family members, biochemical characterization and cellular functions. 3) Mechanisms of regulation of the ubiquitously expressed p- and m-calpains, at the cellular and molecular levels. 4) Physiologic functions of the calpains. 5) Calpains in pathology. Funding is requested to partially support travel expenses and housing for speakers, organizers and promising young investigators. Additional funding will be sought from the Muscular Dystrophy Association, and the USDA, because of calpain involvement in muscular dystrophy and muscle growth. Funding will also be requested from several drug companies which are currently conducting research on calpains. In selecting participants, preference will be given to women and under represented minorities. The speakers include virtually all of the women scientists in the field who have made substantial contributions. Four of the session chairs are women. The Big Mountain resort is a handicapped-accessible facility, and the registration form will question participants about any special needs they may have. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: COORDINATION OF PROCESSING AND TRANSPORT OF MRNA Principal Investigator & Institution: Silver, Pamela A. Professor; Dana-Farber Cancer Institute 44 Binney St Boston, MA 02115 Timing: Fiscal Year 2002; Project Start 01-MAY-1998; Project End 30-APR-2006 Summary: The long-term objective of the proposed research is to understand the mechanism by which mRNAs are exported out of the nucleus. The process of mRNA export includes: proper processing, packaging into protein-RNA complexes, targeting to and movement through the nuclear pore complex and release into the cytoplasm for translation. A transport machinery distinct from that for protein export has been proposed for mRNAs. As with protein import and export, mRNA export can also be regulated by, for example, growth conditions and viral infection. The Specific Aims are to determine how: 1) mRNAs are co- transcriptionally recruited for export; 2) mRNAs are recognized in the nucleus by certain RNA binding proteins; 3) mRNAs are selectively exported under conditions of stress; and 4) protein methylation of RNA binding proteins at arginine affects their activity. Defects in mRNA metabolism that can affect transport are associated with a number of diseases thus contributing to the healthrelatedness of the project. For example, splicing and 3' end formation are associated with a number of diseases including metastatic cancers, muscular dystrophy and amyotrophic lateral sclerosis. In addition, some viruses exploit the endogenous nuclear transport machinery in order to propagate - in some cases by inhibiting export of host in favor of viral messages. Methylation of RNA and DNA binding proteins at arginine has recently emerged as important for many levels of regulation including viral RNA

Studies 21

export, response of cells to interferon and the action of certain RNA binding proteins in motor neuron degeneration in spinal muscular atrophy. Lastly, arginine-methylated proteins such as hnRNPs and myelin basic protein are prominent in autoimmune diseases such as systemic lupus erythematosus and multiple sclerosis. It may be that modified arginine elicits special recognition properties that lead to exacerbation of autoimmune diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--ANIMAL MODELS AND IMMUNOLOGY LAB Principal Investigator & Institution: Bromberg, Jonathan S. Surgical Director; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001 Summary: The central purpose of the Animal Models Core is to provide the affiliated investigators with the appropriate genotype and strain of rodent for the proposed studies, and to provide a range of immunological assays on animals inject with adenoviral vectors. The Animal Models Core is specifically dedicated to investigations of novel strategies of gene delivery to aged or dystrophic striated muscle, as well as mechanistic based evaluations of the effects of genetic modification of dystrophin on muscle cell mechanical properties in young and aged animals. All rodents will be raised and maintained under specific-pathogen-free conditions at the University of Michigan AAALAC-accredited animal facility. In addition to maintaining stocks of animals for testing, the core will conduct a detailed life span analysis of the dystrophic mdx mouse. This core lab will also handle all the immunology required for analysis of adenoviral vector development. A goal of our new vector design is to develop an adenoviral based vector that does not trigger a strong immune response in host animals, particularly a cytotoxic T-cell mediated response. Animals that are injected with virus will be used not only to assess the longevity and functional consequences of gene expression, but will also be tested for potential immune responses against the virus and the transgene being delivered. This analysis will involve CTL-assays against adenoviral and transgene proteins, as well as B cell mediated humoral immune responses against the same proteins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CLINICAL SPECIMEN AND DATA Principal Investigator & Institution: Engle, Elizabeth C. Associate Professor of Neurology; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The four projects in this Program Project share the common theme of characterizing and understanding normal and abnormal patterns of gene expression in developing muscle from the stem cell stage through to maturity. The Program PI?s have a long and extensive history of interaction and have exchanged ideas, biopsy samples, and other reagents over many years. This Program Project is designed to further strengthen these collaborations and to produce synergistic results that are beyond the scope of any one laboratory. The services of the Clinical Specimen and Data Core (Core B) will be one important means by which the Program Project will meet these goals. The techniques required to perform the Aims of this Core are standard within the laboratories of each PI. By centralizing these techniques, formalizing data and tissue collections, and developing a database within the Muscular Dystrophy Research Portal (MDRP), Core B will increase efficiency and provide standardization to the


analysis of data for each Project and the Program overall. Toward this end, the Aims of Core B are designed to maximize efficiency and minimize both administrative and technical effort and expense. Aim 1. Ascertain the Program Project patient and control participants and acquire the comprehensive clinical data, peripheral blood samples, and muscle tissue samples from both patients and controls (Projects served: 1, 2, 3, 4, Core C). Aim 2. Catalogue and track all clinical (Aim 1) and diagnostic data (Aims 1 and 4) pertaining to patients and blood/tissue samples. Annotate and enter all data into the muscular dystrophy research portal (MDRP) (Projects served: 1, 2, 3, 4, Core C). Aim 3. Prepare muscle tissue samples for gene expression analysis. Isolate mRNA and synthesize labeled cDNA/cRNA for hybridization to Affymetrix oligonucleotide and Genetic Microsystems cDNA arrays (Projects served: 1, 2, 3, Core C). Aim 4. Isolate DNA from patient blood samples and provide selective verification of participant's disease mutations (Projects served: 1, 2, 3). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--CONTRACTILITY Principal Investigator & Institution: Faulkner, John A. Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 15-JUL-2001; Project End 30-APR-2002 Summary: The purpose of the Contractility Core is to provide collaborating investigators in the Program Project with reliable and valid measures of the contractile properties of whole striated muscles and of strips of diaphragm muscle fibers, statistical analysis of the data, and interpretation of the structure-function relationships. The Core will also provide opportunities for instruction and training for faculty and trainees who wish to learn the techniques. Muscle fibers when activated attempt to contract or shorten. Whether an activated myofiber shortens, stays at the same length or is stretched depends on the interaction between the force developed and the load. For striated muscle, contractility is defined as the capability of muscle fibers to develop force during fixed length or isometric contractions, during shortening or miometric contractions, and during lengthening or pliometric contractions. Our working hypothesis is that contractility of striated muscles is a complex phenomenon and the provision of reliable and valid measurements requires sophisticated equipment and highly trained muscle mechanicists to make the measurements and analyze and interpret the results. Consequently, to test hypothesis relating the underlying mechanisms of the reduced contractility of striated muscles in diseased and old animals rigorously, a Contractility Core is a necessity. Impairments during each of the three types of contraction may occur at any age due to injury or disease or as an intractable concomitant of aging. The impairments in contractility, whether due to injury, disease, or old age, limit the activities of daily living and reduce the quality of life, particularly for the sick and the elderly. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--FAMILY ASCERTAINMENT, LINKAGE ANALYSIS AND INFORMATICS Principal Investigator & Institution: Pericak-Vance, Margaret A. Professor; Duke University Durham, NC 27706 Timing: Fiscal Year 2001 Summary: The Family Ascertainment, Linkage Analysis, and Informatics Core provides a comprehensive framework for clinical and statistical resources necessary to identify

Studies 23

genes which predispose to human disease. These functions are highly interdependent and critical to the success of linkage studies. Central to both the family ascertainment and statistical components is the PEDIGENE database. PEDIGENE is a relational database that integrates family history, clinical, and genotypic marker results together with DNA banking and genomics that integrates family history, clinical, and genotypic marker results together with DNA banking and genomics functions from Core B. This flexible, highly secure genetic database system continues to be instrumental in the rapid and accurate assimilation of and access to all types of genetic data. This core will serve as the umbrella for coordinating and performing all linkage studies in projects 1 and 3, from initial linkage through characterization of heterogeneity through fine mapping, in Mendelial diseases. These diseases include Charcot-Marie- Tooth disease type 2, familial spastic paraparesis, the autosomal dominant limb-girdle muscular dystrophies, facioscapulohumeral muscular dystrophy, and the Lumbee myopathy. The Core also provides consulting support for complex trait analysis such as in project 2, including non-parametric linkage analysis (siblink) and TDT. In addition, this core provides seed support for several projects under development including studies of neural tube defects and Chiari type 1 malformation. Ultimately, these projects will be developed to a point to ensure independent funding, thereby maximizing the impact of the availability of these critical core resources. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--MUSCLE PHYSIOLOGY Principal Investigator & Institution: Watchko, Jon F.; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2001 Summary: The Muscle Physiology Core is a well equipped in vitro physiology laboratory staffed with experienced personnel skilled in executing personnel skilled in executing the proposed contractile studies. This Core will be supervised by Jon Watchko, M.D., and be available to all principal investigators assisting them in achieving their research goals evaluating the effects of gene therapy on skeletal muscle function. In addition to meeting the overlapping needs of individual projects and thereby being the most efficient use of space, equipment and personnel talent, this Core will enhance collaboration between investigators. The Specific Aims of the Muscle Physiology ore are to i) obtain natural history data on muscle function of the tibialis anterior in normal and dystrophic (dystrophin-deficient mdx) mice, and normal and dystrophic cardiomyopathic) hamsters, and ii) determine the positive or negative effects of viral vector gene delivery on contractile function of the tibialis anterior muscle of dystrophin deficient mice and delta- sarcoglycan hamsters. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CRYSTALLOGRAPHIC POLY(A)POLYMERASE

STUDIES

OF

EUKARYOTIC

Principal Investigator & Institution: Doublie, Sylvie; Microbiol & Molecular Genetics; University of Vermont & St Agric College 340 Waterman Building Burlington, VT 05405 Timing: Fiscal Year 2001; Project Start 18-DEC-2000; Project End 30-NOV-2005 Summary: (From the applicant's abstract) The long-term goal of this project is to understand the molecular mechanisms of eukaryotic mRNA polyadenylation. mRNA polyadenylation plays an essential role in the initiation step of protein synthesis, in the export of mRNAs from the nucleus to the cytoplasm, and in the control of mRNA


stability. Polyadenylation is a key regulatory step in the expression of many genes. Aberrant polyadenylation has been shown to cause diseases such as thalassemia and lysosomal storage disorder. Moreover, oculopharyngeal muscular dystrophy is the result of the insertion of short GCG repeats in the gene encoding one of the polyadenylation factors, poly(A) binding protein 2 (PABP 2). We are investigating the crystal structure of the enzyme at the heart of the polyadenylation machinery, poly(A) polymerase (PAP), its interaction with substrates, and its association with proteins playing a part in mRNA 3'-end processing. There are no structural data to date for any of the mammalian polyadenylation factors. The specific aims are as follows: 1. The X-ray crystal structure of bovine PAP with its substrates ATP and poly(A) RNA will be determined using a combination of multiwavelength anomalous diffraction (MAD) and multiple isomorphous replacement. The structure of PAP complexed with substrates will guide additional structural and functional studies. 2. PABP 2 is required for processive synthesis and control of the poly(A) tail length. PABP2 is known to bind both the poly(A) tail and PAP. We will work towards the structure determination of the ternary complex of PABP2, PAP, and poly(A), using either the intact proteins or the interacting domains of each protein. 3. Phosphorylation of target sites located in the Cterminal domain of PAP results in strong repression of PAP activity. The down regulation of PAP via hyperphosphorylation is reminiscent of the inhibitory effect of U1A, which has been shown to inhibit polyadenylation of its own mRNA by binding to PAP. We will work towards the crystallization of the complex between PAP and U1A, using either the intact proteins, or the C-termini of each protein. We will concurrently attempt to crystallize phosphorylated, full-length bovine PAP. A comparison of the phosphorylated PAP structure with that of the PAP-U1A complex should elucidate whether both situations use a similar mechanism of repression. It is expected that these results will not only provide a sound structural basis for understanding the mechanism of polyadenylation at the molecular level but will also shed light on the mechanisms of processivity and repression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINESIS AND CELL POLARITY IN C ELEGANS EMBRYOS Principal Investigator & Institution: Bowerman, Bruce A. Associate Professor; None; University of Oregon Eugene, OR 97403 Timing: Fiscal Year 2001; Project Start 01-MAY-1999; Project End 30-APR-2003 Summary: We propose to use the powerful genetics and the impressive cytological properties of the early C. elegans embryo to investigate cytokinesis and its relationship to mitotic spindle orientation in a developing animal. The early C. elegans embryo offers two key advantages for these studies: (i) the ability to rapidly identify genes required for cytokinesis and for mitotic spindle orientation in early embryonic cells, and (ii) the ability to visualize with high resolution the subcellular localization of functionally important proteins in the large (approximately 22 x 55 micron) 1-cell stage zygote. We have three long term goals: (1) To use genetic and molecular methods to define cytokinesis as a series of discrete molecular interactions that execute cytokinesis in the early embryo. (2) To determine the mechanistic relationship between the termination of cytokinesis and the mechanisms that orient mitotic spindles during asymmetric divisions in early embryonic cells. (3) To identify motor proteins important for cytokinesis and the generation of asymmetric cell divisions. These studies will provide significant insight into the molecular basis for human pathologies: cytoskeleton/plasma membrane interactions have proven relevant to our understanding of cancer and of other significant diseases, including muscular dystrophy, deafness, and sterility. In

Studies 25

preliminary studies, we have identified a gene called cyk-1 that is required for a late step in cytokinesis. This is the first gene identified in C. elegans that is specifically required for cytokinesis in the early embryo. Intriguingly, the CYK-1 protein localizes to the leading edge of the cleavage furrow late in cytokinesis, where we hypothesize it bridges the actin and tubulin cytoskeleton. While CYK-1 provides a starting point for identifying functionally protein/protein interactions that occur during cytokinesis, we first propose to identify as comprehensively as possible the genes required for cytokinesis and mitotic spindle orientation. To this end, we have begun a large-scale screen for temperature-sensitive, embryonic-lethal mutants, and we are using a functional genomics approach that involves the use of a recently discovered technology called RNA interference. We will molecularly clone genes that are most specifically required for cytokinesis and mitotic spindle orientation. By using genetic and molecular epistasis experiments, and by examining how the different proteins we identify interact, we will define the molecular interactions and pathways that control these fundamental cellular and developmental processes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOSKELETAL INTERACTIONS OF DYSTROPHIN Principal Investigator & Institution: Ervasti, James M. Professor; Physiology; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 15-JUL-1994; Project End 31-MAR-2005 Summary: (Verbatim from the Applicant's Abstract): The objective of this project is to determine the cytoskeletal interactions of the dystrophin-glycoprotein complex in the skeletal muscle to understand how its absence or abnormality leads to Duchenne (DMD) and Becker (BMD) muscular dystrophies and some forms of cardiomyopathy. Rather than just simply serving to anchor its associated glycoprotein complex to the cortical actin, our previous studies lead us to hypothesize that dystrophin also plays an important role in stabilizing the cortical cytoskeleton through an extended lateral association with actin filaments. We further hypothesize that the dystrophin homologue utrophin is missing an actin binding suite important for F-actin stabilization. These hypotheses will be tested, both in vitro and in vivo, through the pursuit of 3 complementary specific aims. The F-actin binding properties of full-length and truncated forms of recombinant dystrophin and utrophin will be measured by established biochemical and spectroscopic procedures (Aim 1). Completion of this aim will yield the first direct structure/function comparison for dystrophin and utrophin up-regulation to effectively compensate for dystrophin deficiency. Recombinant dystrophin/utrophin will be visualized alone and in complex with actin filaments using electron microscopy combined with three-dimensional reconstruction techniques (Aim 2). These studies will yield important new information about the shape, dimensions and flexibility of dystrophin and utrophin and will independently determine how much (and which sub-domains) of dystrophin lie in close apposition with F-actin. Analysis by three-dimensional reconstruction will also identify changes in actin monomer and filament structure that may lead to more stable association of other costameric proteins with F-actin. Finally, we will relate the in vitro features of the dystrophin/F-actin interaction with its role in stabilizing costomeric actin in vivo (Aim 3). Sarcolemmal membranes will be mechanically isolated from muscles of transgenic mdx mice expressing dystrophin constructs deleted in different domains and the status of costameric actin determined by confocal microscopy. We will also determine whether the absence of dystrophin results in an unstable sarcolemmal association of other costameric actin binding proteins. Completion of these aims will result in a highly


detailed and integrated understanding of dystrophin's role in stabilizing the muscle membrane cytoskeleton through its interaction with cortical actin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHWAY

CYTOSOL/VESICLE/VACUOLAR

PROTEIN

DEGRADATION

Principal Investigator & Institution: Chiang, Hui-Ling; Cellular/Molecular Physiology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, PA 17033 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 31-AUG-2002 Summary: Protein degradation is important for cell cycle control, signal transduction and cell growth. Abnormal protein degradation has been implicated in metabolic disorders, cancer development and muscular dystrophy. A novel pathway of protein degradation in the yeast vacuole has been established in our lab. They key gluconeogenic enzyme, fructose-1.6- biophosphatase (FBPase), is targeted from the cytosol to the yeast lysosome (vacuole) for degradation when Saccharomyces cerevisiae are replenished with glucose. Our long term goal is to understand the FBPase degradation pathway. We have reconstituted this glucose-regulated targeting pathway using semi-intact cells, purified FBPase, an ATP regenerating system and cytosol. FBPase is targeted to the vacuole in the reconstituted system. We have isolated 33 vid (vacuolar import and degradation) mutants defective in the glucose-induced degradation of FBPase. Mutant analysis led to the hypothesis that FBPase is targeted from the cytosol to the intermediate vesicle and then the vacuole for degradation. We have purified a novel FBPase-associated vesicle to near homogeneity. We cloned the VID24 gene involved in vesicle targeting to the vacuole. Vid24p is synthesized and localized to the vesicles. Our specific aims are: (1) Reconstitution of FBPase import into the vesicle using the vid24-1 mutant. We will examine whether the imported FTPase is indeed targeted to the intermediate vesicles. We will divide vid1-vid13 which accumulates FBPase in the cytosol into functional subgroups. (2) Cloning of the VID genes. We plan to clone the VID genes using the colony blotting procedure and study the expression and localization of the Vid proteins. As an alternative approach, we will clone the VID15 gene which is tightly linked to the URA3 gene by chromosomal walking. (3) Purification of cytosolic proteins required for FBPase import into the vesicles. We will use the vid1-vid13 mutants that contain defective cytosolic factor(s) and add fractionated wild type cytosol to identify the fractions that complement the mutant cytosol defect. If we identify such protein, we will make mutants and prepare cytosol from the mutants to test whether the cytosol is defective in FBPase import in vitro. We will examine whether FBPase import into the vesicles is regulated by ATP or GTP hydrolysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DB TRIAL OF PROVENTIL IN FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY Principal Investigator & Institution: Kissel, John; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, OH 43210 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DETERMINANTS OF MYOGENIC AND NEURONAL MEMBRANE PHENOMENA Principal Investigator & Institution: Horwitz, Alan F. Professor and Head; Cell Biology; University of Virginia Charlottesville Box 400195 Charlottesville, VA 22904 Timing: Fiscal Year 2001; Project Start 01-JAN-1988; Project End 31-DEC-2002 Summary: Skeletal muscle is an ideal system with which to study adhesion molecules and the membrane-cytoskeletal linkages in which they participate as they play a central role in muscle development, structure and physiology, and pathology. Once muscle precursors have migrated to their targets, the program of terminal differentiation commences, which is regulated by the extracellular matrix. An elaborate contractile apparatus is synthesized and organized, which contains several cell surface associations including the myotendinous and costomeric junctions. Muscle cells are innervated at neuromuscular junctions. It is now clear that dystrophin, the muscular dystrophy gene product, has homologies to cytoskeletal proteins and is associated with adhesion molecules like integrin. The integrin family of receptors for extracellular matrix molecules are implicated in all of the above phenomena by virtue of their localization in junctional regions, their functions as dual receptors for extracellular matrix and cytoskeletal molecules, and as mediators of signal transductions. The hypothesis that guides our current research is that the integrins play a central role in organizing the surface, the extracellular matrix, and the contractile apparatus of skeletal muscle and in addition mediate signals from the extracellular matrix triggering its differentiation. Our general aims for the project period are to identify and characterize the amino acid sequences on integrin cytoplasmic and extracellular domains that determine the organization of junctional regions and determine their role in adhesion. This will be done using a recently constructed library of single-amino acid substitutions in the Beta1cytoplasmic domain and synthetic peptides corresponding to active and mutant sequences. A similar library will be constructed for alpha subunits. Analogous, but different, methods are proposed to find extracellular matrix binding sequences in the extracellular domain. The second major aim is to identify and purify novel integrin associated cytoplasmic proteins. Previous specificity problems will be addressed using peptide sequences derived from mutant and wild type cytoplasmic domain sequences. Recently we have identified two novel integrin associated molecules. Both are cytoskeletal and one is a complex of 5 proteins. They will be characterized further for binding specificities and localization on muscle. The third objective is to elucidate the role of integrins in organizing and stabilizing junctional regions. This will be done using molecular genetic techniques to identify functional domains, alter regulation of expression, and reduce or eliminate the expression of specific integrins. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DISINTEGRINS & METALLOPROTEINASES IN ORTHOPEDIC DISEASE Principal Investigator & Institution: Smith, Jeffrey W.; Burnham Institute 10901 N Torrey Pines Rd San Diego, CA 92037 Timing: Fiscal Year 2001; Project Start 01-APR-1994; Project End 31-MAR-2003 Summary: (Adapted from the Applicant's Abstract): The events leading to cell-cell fusion are key to the development and homeostasis of bone and muscle. The broad objective of this study is to understand the mechanisms that lead to the differentiation and fusion of osteoclasts and myotubes. Results from the study could lead to new treatments for osteoporosis and muscular dystrophy. The hypothesis of the proposal is


that a recently discovered family of transmembrane proteins, called ADAMs, are important in the differentiation of bone and muscle. The ADAMS contain A Disintegrin And Metalloproteinase domain. The study will initially focus on meltrin-alpha, an ADAM expressed by myoblasts and osteoclasts. One objective of the study is to perform the first characterization of the biosynthesis and cellular localization of meltrin-alpha. These experiments will determine if the metalloproteinase domain of meltrin is released from the cell surface, and whether meltrin-alpha co-localizes with integrin in focal adhesion sites. A second objective will be to determine how each domain of meltrinalpha is involved in the fusion of myoblasts. In this analysis, site-directed mutagenesis and polyclonal antibodies will be applied to ablate the biochemical activity of domains of meltrin, and the effects of these manipulations on myogenesis will be assessed. A third objective is to examine the structure-function relationships of the metalloproteinase and disintegrin domains of meltrin-alpha. Phage-display will be used to build inhibitors of the metalloproteinase. Studies will be conducted to identify the cell surface receptor for the disintegrin domain of meltrin-alpha. A final objective is to identify the ADAM proteins present in osteoclasts and their precursors. Homologybased PCR will be used to clone osteoclast ADAMs. Antibodies against these ADAMs will be used in attempts to block osteoclast differentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISULFIDE STRUCTURE OF BIOMEDICALLY IMPORTANT PROTEINS Principal Investigator & Institution: Watson, Jack T. Associate Professor; Biochemistry; Michigan State University 301 Administration Bldg East Lansing, MI 48824 Timing: Fiscal Year 2001; Project Start 01-FEB-2001; Project End 31-JAN-2005 Summary: Disulfide bonds are a critically important determinant of the shape and, thus, the activity of some biomedically important proteins. The common bleeding disorder, von Willebrand Disease, appears to be related to a defect in the disulfide bonding pattern among 18 cysteines (including two pairs of adjacent cysteines) of a particular protein (VWF) that disrupts the normal blood clotting cascade. Very little is known about the cysteine status of the von Willebrand protein (VWF), and such knowledge will help explain the cause of this disorder at the molecular level; however, VWF is resistant to the conventional proteolytic approach to disulfide mapping. Knowledge of the disulfide bonding pattern in the receptor- binding proteins for TGF-beta will help provide an important 'template' for the development of drugs (antagonists) for treatment of fibrotic disorders ,e.g., Duchennes muscular dystrophy; similarly, the development of other drugs (agonists) may serve as anti-cancer agents by promoting the negative proliferative response to TGF-beta. However, the highly knotted, cysteine-rich (up to 12 cysteines, 3 of which are adjacent) receptor-binding proteins for TGF-beta are resistant to conventional disulfide mapping. Developing a protocol for the disulfide mapping of VEGF homodimer will provide the basis for designing and monitoring the proper folding of related pharmaceutical proteins with angiogenic activity. Our novel approach to disulfide mapping, based on cyanylation of and cleavage at cysteine residues, offers new hope for determining the disulfide bonding pattern of the biomedically important cystinyl proteins described above that are refractory to conventional methodology. Cyanylation is selective for free sulfhydryls and can be accomplished at pH 3, a condition that suppresses problems with disulfide scrambling. We have demonstrated that the cyanylation/cleavage approach is applicable to proteins containing adjacent cysteines, an attribute that recommends it for successfully attacking the difficult analytical challenges posed by the proteins described herein. An a1gorithm

Studies 29

will be developed to assign the connectivity of cysteines in disulfide bonds given an input of amino acid sequence and mass spectra of cyanylation/cleavage products. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DMD GENE THERAPY USING HSV/AAV HYBRID VECTOR SYSTEM Principal Investigator & Institution: Wang, Yaming; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001; Project Start 15-AUG-2000; Project End 31-JUL-2003 Summary: The principle investigator for this proposal, Dr. Yaming Wang, is an Instructor in Anesthesia at Brigham and Women's Hospital and Harvard Medical School. The work outlined in this proposal will serve to fund the mentored transition of Dr. Wang into gene therapy of muscular diseases and from a research associate to an independent academic investigator and application R01 level funding. The mentor in this proposal, Dr. Allen is an independent clinical scientist with extensive published experience in the area of muscle biology. A mentor committee consisting of Dr. Allen and three other scientists (Dr. Breakefield, Dr. Kunkle, and Dr. Leboulch) will serve as the advisory committee for Dr. Wang and will carefully oversee her progress. The environment in which the proposed work will be carried out (Harvard Medical School) is a world class scientific community where biomedical research is performed at the highest level with intimate associations between clinical and basic science disciplines. In this proposal, Dr. Wang will investigate the effectiveness of an exciting novel hybrid HSV/AAV amplicon virion expressing dystrophin as a possible solution to the problems facing the currently proposed and active gene therapy protocols for a common X-linked myopathy, Duchenne's Muscular Dystrophy (DMD). Current therapy has failed because it has been unsuccessful in obtaining durable expression of the transferred gene product. There were a number of reasons for this failure, such as cytotoxicity, immune reactions caused by with viral gene expression and virion proteins, and non-integration of vector DNA. She has demonstrated that the HSV-1 amplicon virions are capable of transducing skeletal muscle myofibers in vivo and myoblasts and myotubes in vitro using both GFP and dystrophin as the experimental marker gene. Both GFP and dystrophin virions were shown to permanently transduce myoblasts in culture at a low frequency (0.5-2 percent) suggesting their ability to integrate into the host genome. As a work in progress she has designed new amplicon vectors capable of carrying the 14kB dystrophin cDNA, GFP and an antibiotic selection marker, and has demonstrated that these amplicons can be packaged into HSV virion particles that can induce transcription of the appropriate protein in mdx myotubes. The overall aim of this project is to create a new nontoxic, high efficiency and long term transgene expression AAV/HSV-1 hybrid vector system to express dystrophin in a mdx mouse animal model to attempt DMD phenotype correction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DUAL AAV VECTORS FOR DUCHENNE MUSCULAR DYSTROPHY THERAPY Principal Investigator & Institution: Duan, Dongsheng; Assistant Prof. of Microbio & Immunology; Molecular Microbiol and Immun; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2003; Project Start 14-JUL-2003; Project End 30-APR-2008 Summary: (provided by applicant): Duchenne muscular dystrophy (DMD) is the most common form of inherited muscle disease. It usually leads to death from respiratory or


cardiac failure by age 20. Currently, no effective treatment is available for this fatal disease. DMD is an X-linked genetic disease caused by dystrophin gene mutation. Gene therapy represents a very promising avenue to cure DMD. Recombinant adenoassociated virus (rAAV) mediates high-level persistent transgene expression in muscle. Recent clinical trials have further confirmed the efficiency and the safety of rAAV vectors in muscle. However, rAAVmediated DMD gene therapy has been significantly limited by the small viral packaging capacity. Only the highly truncated C-terminaldeleted versions of "micro-dystrophin" genes have been attempted. Both clinical and transgenic studies show that the C-terminal-inclusive larger genes (such as the 6.0-6.3kb "mini-dystrophin" genes and the approximately 4.7kb "C-terminal-inclusive microdystrophin" genes) are therapeutically superior. Unfortunately the strong therapeutic expression cassettes derived from these genes are too large to be packaged in a single AAV virion. We have recently developed several dual vector approaches to expand AAV packaging capacity. Among these, the concatamerization-based "trans-splicing" and "cis-activation" strategies hold great promise for delivering the C-terminal-inclusive larger dystrophin genes. However, the expression level achieved so far is not sufficient for DMD gene therapy. In this proposal, we plan to extend our previous findings and further explore the molecular mechanisms underlying these methods, in the hope of improving the transduction efficiency for DMD gene therapy. In particular, we will try to identify and overcome the rate-limiting barriers to transgene expression. These include problems associated with dual vector co-infection, concatamerization of AAV genome inside cell, and transcription, splicing, and stability of AAV concatamers. More important, we will apply this newly obtained information to generate the most effective trans-splicing and cis-activation AAV vectors for the C-terminal-inclusive larger dystrophin genes. Therapeutic potentials of these newly developed AAV vectors will be rigorously tested in the limb muscle, diaphragm, and heart of the murine DMD model (mdx mouse). A comprehensive array of assays will be used to examine the level of gene expression and the functional improvement in muscle histology and contraction. To address safety concerns, we also plan to evaluate the potential deleterious effects from putative truncated protein production in the trans-splicing method. Taken together, our findings will lead to the eventual application of these very promising dual AAV vector strategies to the human DMD gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYSTROPHIN REPLACEMENT IN MDX MICE Principal Investigator & Institution: Chamberlain, Jeffrey S. Professor; Neurology; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 01-APR-1991; Project End 31-MAR-2005 Summary: (Adapted from applicant's abstract): Duchenne muscular dystrophy (DMD) is an X-linked recessive, lethal disorder caused by mutations in the dystrophin gene. Considerable progress has been made both in understanding the function of dystrophin, and in demonstrating the feasibility of gene therapy for DMD. Nonetheless, numerous obstacles remain before gene therapy can be effectively applied to this common genetic disease. These obstacles include a lack of data on the reversibility of the dystrophic pathology, limited ability of viral vectors to carry the enormous dystrophin gene or cDNA, and questions about the effectiveness of inefficient delivery methods of dystrophin vectors. This application proposes to address these concerns by generating several novel strains of transgenic mice. The ability to modulate the dystrophic phenotype will also be explored using viral delivery of dystrophin and several death protectors to mdx mice, a model for DMD. Transgenic mice that express moderate levels

Studies 31

of dystrophin are able to prevent the development of dystrophy in the mdx mouse, a model for DMD. Delivery of adenoviral vectors expressing truncated dystrophins to neonatal, immune tolerant mice can also prevent muscular dystrophy near the site of injection. However, it has not been possible to demonstrate that the pathology can be halted or reversed in adult, dystrophic animals. Aim1 will address the feasibility of reversing muscular dystrophy at different stages of the disease by studying a transgenic mouse line that displays tetracycline-inducible dystrophin expression. Aim 2 will continue previous work aimed at understanding the structural basis of dystrophin functional domains, with the goal of developing severely truncated cDNAs that can be carried by a variety of promising viral vectors, such as adenoassociated viruses (AAV). Currently, the only vectors capable of carrying the full-length dystropin cDNA have problems with cytotoxicity, immune rejection or low titers. AAV efficiently infect muscle with no immune response, but have a limited cloning capacity. Aim 3 explores the ability to modulate dysrtophy by delivery of dystrophin with proteins that repress apoptosis and/or enhance muscle regeneration. Achieving uniform and efficient gene delivery to muscles using viral vectors is a daunting goal. The ability to modulate dystrophy and prolong muscle fiber longevity could greatly facilitate the effectiveness of dystrophin gene replacement strategies. These studies will provide new insights into both the structure of dystrophin and the mechanisms of dystrophic cell death and will help advance the development of gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DYSTROPHIN-GLYCOPROTEIN COMPLEX IN CARDIOMYOPATHY Principal Investigator & Institution: Michele, Daniel E. Physiology and Biophysics; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The long term objective of this proposal is to understand the molecular basis of inherited cardiomyopathies, particular those associated with mutations in components of the dystroglycan-glycoprotein complex. The dystroglycan-glycoprotein complex provides a link from the cytoskeleton to the extracellular matrix. Mutations in components of this complex, such as delta sarcoglycan, cause recessive forms of muscular dystrophy. Interestingly, heterozygous mutations in the same delta sarcoglycan can also cause dilated cardiomyopathy without muscular dystrophy. The basis for the tissue specificity of these mutations and the mechanism behind sarcoglycan associated dilated cardiomyopathy is unclear. Furthermore, muscular dystrophy patients with mutations in enzymes that glycosylate dystroglycan and whose activity is necessary for dystroglycan to bind extracellular ligands, also have a high prevalence of cardiomyopathy. This proposal tests the hypothesis that the link between the cytoskeleton and the extracellular matrix 'through dystroglycan, specifically in cardiac myocytes, is critical 'to the development of cardiomyopathy. The proposed research will test the dominant-negative and tissue specific effects of delta sarcoglycan mutations on the attachment of alpha-dystroglycan to the transmembrane complex using isolated muscle cell gene transfer. In addition, the tissue specific role of dystroglycan glycosylation in the link to the extracellular matrix and the development of cardiomyopathy will be tested in the myodystrophy mouse. Finally, tissue specific gene targeted mice will be generated to determine if the link from cytoskeleton to matrix through dystroglycan, is necessary and sufficient in a tissue specific manner, to cause and explain the development of DGC associated cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: DYSTROPHIN-GLYOPROTEIN CARDIOMYOPATHY

COMPLEX

AND

DILATED

Principal Investigator & Institution: Knowlton, Kirk U. Associate Professor; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, CA 92093 Timing: Fiscal Year 2001 Summary: Dilated cardiomyopathy is a multi-factorial disease that includes both the hereditary and acquired forms of cardiomyopathy. Recent experiments have shown that hereditary cardiomyopathy in humans can be associated with genetic defects in components of the dystrophin-glycoprotein complex. For example, mutations in the dystrophin gene lead to a high incidence of cardiomyopathy in Duchenne and Becker muscular dystrophy, and can caused X-linked dilated cardiomyopathy. Mutations in the genes for the sarcoglycans are responsible for limb girdle muscular dystrophy and are often quite associated with cardiomyopathy. In addition, our preliminary data links an acquired form of cardiomyopathy, enteroviral infection, with disruption of the dystrophin-glycoprotein complex. Thus, evidence is accumulating that the dystrophinglycoprotein complex has a critical role in the genesis of hereditary and acquired cardiomyopathy. Dystroglycan is a key component of the dystrophin- glycoprotein complex that links the cytoskeletal protein dystrophin to the extracellular matrix protein laminin-2. Recent experiments with dystroglycan null ES cells have demonstrated that dystroglycan is required for basement membrane assembly but not cardiac myocyte differentiation. Sarcoglycans interact closely with dystroglycan and recent studies of sarcoglycan null mice have suggested that the underlying mechanism of sarcoglycan related cardiomyopathy is due to the dysfunction of vascular smooth muscle. The overall goal of this project is to test the hypothesis that the dysfunction of the dystrophin-glycoprotein complex can lead to dilated to dilated cardiomyopathy. We plan to test the following three hypotheses: 1) disruption of dystroglycan in the cardiac myocyte is sufficient to disrupt normal basement membrane assembly and induce cardiomyopathy; 2) disruption of sarcoglycan function in the vascular smooth muscle is sufficient and necessary to induce the cardiomyopathy that occurs with genetic alteration of the vascular smooth muscle is sufficient and necessary to induce the cardiomyopathy; 2) disruption of sarcoglycan function in the vascular smooth muscle is sufficient and necessary to induce the cardiomyopathy that occurs with genetic alteration of the sarcoglycan complex; and 3) cleavage of dystrophin in the cardiac myocyte contributes significantly to to the cardiomyopathy of enteroviral infection. To directly examine dystroglycan's function in the heart we have proposed experiments in the first specific aim to circumvent the early lethality of dystroglycan null mutation in order to analyze dystroglycan's role in cardiac basement membrane assembly and cardiac function. The second aim is to investigate the regulation of the dystroglycan complex by the sarcoglycans in vascular smooth muscle of the heart. For this aim mice with a specific deficiency in delta-sarcoglycan in smooth muscle will be produced. Specific aims three and four identify the mechanisms of enteroviral protease 2A mediated cleavage of dystrophin and determine the significance of this cleavage in the intact heart. The complimentary approach is outlined in these specific aims will yield a new understanding of the role of dystrophin-glycoprotein complex in both hereditary and acquired cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies 33

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Project Title: EFFICACY AND SAFETY OF OXANDROLONE FOR BOYS WITH DUCHENNE'S MUSCULAR DYSTROPHY Principal Investigator & Institution: Pestronk, Alan; Professor; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EMERIN FUNCTIONS IN TRANSCRIPTIONAL REGULATION Principal Investigator & Institution: Holaska, James M. Cell Biology and Anatomy; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2003; Project Start 01-MAY-2003; Project End 30-APR-2005 Summary: (provided by applicant): The presence of the nuclear envelope in eukaryotes functionally separates the processes of transcription and translation. The ability to have these processes disjoined serves to establish greater transcriptional and translational regulation. The nuclear envelope consists of an outer nuclear membrane, which is contiguous with the endoplasmic reticulum, and an inner nuclear membrane (INM). The INM contains numerous integral membrane proteins that bind to both lamins and chromatin-associated proteins. One of these proteins, emerin, directly binds the nuclear lamina and a chromatin associated protein named Barrier-to-Autointegration (BAF). Interestingly, mutation or deletion of emerin causes the recessive form of EmeryDreifuss muscular dystrophy (EDMD). Although emerin is expressed in most cell types tested, EDMD specifically targets muscle and adipose tissue, suggesting a role for emerin in tissue-specific functions. Recently it has been demonstrated that another INM protein, Lap213, interacts with a transcriptional repressor, germ-cell-less (GCL). Since Lab2beta and emerin share a significant region of homology, I tested whether emerin could interact with transcriptional repressors. Both GCL and EBP1, another transcriptional regulator, bind emerin. I propose that emerin may recruit transcriptional regulators to the nuclear envelope and form functional repressor or activator complexes here. To test this model, I will fine-map the functional domains within emerin, GCL, and EBP1 necessary for this interaction. Using mutational analysis, I will identify the domain(s) in emerin that interact(s) with GCL and EBP1. Mutations will also be made in GCL and EBP in order to map the 'emerin binding domain' in each of these proteins. Once identified, the(se) emerin binding domain(s) will be used to identify other emerin binding proteins. The initial characterization of these interactions will serve as the foundation for studying the role of the nuclear envelope in transcriptional regulation in my own laboratory. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENHANCEMENT OF MYOBLAST CHEMOTACTIC MIGRATION Principal Investigator & Institution: Dominov, Janice A.; Boston Biomedical Research Institute 64 Grove St Watertown, MA 02472 Timing: Fiscal Year 2002; Project Start 26-SEP-2002; Project End 30-JUN-2004 Summary: (provided by applicant): Genetic defects underlying several degenerative muscle diseases such as Duchenne muscular dystrophy (DMD) are known, yet effective therapies for these disorders have not been found. One approach has been cell-based therapy in which normal myoblasts or genetically modified patient myoblasts are injected into diseased muscle with the intent that engraftment would be sufficient to


compensate for protein deficiencies. Little success has been achieved with this approach however due to problems such as poor graft survival and impractical requirements for numerous muscle injections. Recently, systemic delivery of muscle precursor cells via tail vein or arterial injection in mice has been demonstrated resulting in low-level donor cell engraftment of regenerating muscle tissue. Vascular migration and extravasation of precursor cells thus occurs and could provide a useful route for improved cell-based therapy for these devastating diseases. The specific aims of the proposed work are to 1) Identify molecules expressed in myoblasts that are involved in the attachment to activated endothelial cells and promote trans-endothelial cell migration, 2) Improve the efficiency of myoblast trans-endothelial migration, if possible, by cytokine-induced expression of molecules known to regulate attachment and extravasation of immune system cells. Methods: Murine skeletal muscle myoblasts will be studied to determine expression levels of proteins known to function in leukocyte extravasation. Inflammatory cytokines will be used to induce myoblast expression of proteins relevant to chemotactic movement. In vitro trans-endothelial cell migration assays will be used to assess the role of specific chemokines, receptors and cell adhesion molecules in this process and the influence of inflammatory cytokine stimulation on myoblast migration. Normal myoblasts and those induced by cytokines will be injected into tail veins of mdx mice (model for DMD) undergoing muscle regeneration and extravasation into tissues assessed. Results will further our understanding of the mechanisms that promote systemic engraftment of donor myoblasts into diseased muscle could significantly advance the therapeutic use of myogenic precursor cells for the treatment of muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EPSILON-SARCOGLYCAN & PATHOGENESIS OF MUSCULAR DYSTROPHY Principal Investigator & Institution: Kobayashi, Yvonne M. Cardiovascular Center; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2002; Project Start 05-AUG-2002 Summary: (provided by applicant): The long-term objectives of this research proposal are to elucidate the function of epsilon-sarcoglycan within the epsilon-beta-gamma-delta sarcoglycan complex, as well as at the sarcolemma, and how its function works together with the functional role of the dystrophin-glycoprotein complex in the pathogenesis of muscular dystrophy. Epsilon-sarcoglycan has 43 percent amino acid sequence identify with alpha-sarcoglycan, and like alpha-sarcoglycan, interacts with beta-gamma, and delta-sarcoglycans at the sarcolemma. In genetically engineered alpha-sarcoglycan deficient mice, there is a decrease in beta-gamma- and delta-sarcoglycans at the sarcolemma, but no change in epsilon-sarcoglycan. However, in beta- and gammasarcoglycan deficient mice, there is little to no detection of beta-, gamma-, and deltasarcoglycans and a severe decrease in epsilon-sarcoglycan at the sarcolemma. These data indicate that epsilon-sarcoglycan forms a separate complex with beta-, gamma-, and delta-sarcoglycans and suggests that epsilon-sarcoglycan plays a pivotal role in the pathogenesis of muscular dystrophy. To test this hypothesis, I have proposed the generation and analysis of different genetically modifiable systems: gene-targeted disruption of epsilon-sarcoglycan in mice, transgenic epsilon-sarcoglycan mice with targeted over expression in striated muscle, and embryonic stem cells homozygous for the deletion of epsilon-sarcoglycan. I also describe the use of epsilon-sarcoglycan recombinant adenovirus for adenovirus-mediated focal gene transfer to rescue the sarcoglycan complexes? functions. Furthermore, I describe the characterization of the

Studies 35

interactions between the sarcoglycan components to further understand the structural and functional relationship between the sarcoglycan components to further understand the structural and functional relationship between the components of the epsilon-betagamma-delta sarcoglycan complex and how this compares to that of the alpha-betagamma-delta sarcoglycan complex. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EVALUATION OF CLINICAL APPLICATIONS OF ELASTOGRAPHY Principal Investigator & Institution: Garra, Brian; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, TX 77225 Timing: Fiscal Year 2001 Summary: The objectives of the project are to demonstrate in a statistically valid number of patients, the clinical utility of the new technique of ELASTOGRAPHY is an adjunct diagnostic tool for the diagnosis of benign and malignant breast masses. Currently, mammography is the primary screening tool for the diagnosis of breast cancer. It is sensitive but often not very specific with approximately 75% of the masses biopsied being non-cancerous. Recently sonography has been shown to be a useful tool for distinguishing solid from cystic masses and for diagnosis solid masses. But often the sonographic features that distinguish benign form malignant masses are subtle and subjective in nature. Elastography is a technique that uses the raw ultrasound signal to produce an image of HARDNESS of breast tissue rather than the normal sonographic image of backscatter intensity. Because breast cancers have long been known to be significantly harder than normal breast tissue and benign breast masses, elastography promises to be helpful in distinguishing benign from malignant masses. Preliminary studies in over 100 patients with biopsy proven breast masses has shown that elastography can reliable identify breast cancers and can distinguish cancers from benign masses in most cases. Using a subjective index of brightness on the elastogram plus the difference in transverse dimension on a mass on elastography and sonography, 11 of 15 benign masses could be classified as definitely benign without incorrectly classifying any cancers as benign. Using these two features, the area of the ROC curve (Az) was 0.86 performance similar to the PAP smear for cervical cancer. The number of cases in the preliminary study was small and only a single observer was used. The current proposal outlines a two center unblinded level of suspicion trial that will demonstrate whether elastography plus mammography and sonography increases the diagnostic confidence of readers for breast cancer and benign masses. Also, a blinded rereading study is proposed that will demonstrate the performance of each modality alone and in conjunction with the other modalities. The number of patients to be studied (about 750) will be sufficient to estimate Az to a standard deviation of 0.02. Since elastography also may be helpful in other organs such as the thyroid, renal transplants, lymph nodes and muscles, pilot studies to evaluate the potential value of elastography in those organs are also proposed. The overall hypothesis is: Elastography is capable of differentiating normal and abnormal tissues, including cancer, in an in vivo clinical environment. The overall hypothesis is: Elastography is capable of differentiating normal and abnormal tissues, including cancer, in an in vivo clinical environment. Specific Aims of the Project are: 1. Establish and define the elastographic properties of normal and abnormal breast tissue in vivo. 2. Conduct a clinical study to explore the potential role of elastography in breast cancer diagnosis. 3. Explore in vivo elastography animal models of normal and abnormal tissues. Specific studies will include normal canine prostate, canine prostate carcinoma, and woodchuck hepatoma models. 4.


Explore the application of elastography to other superficial organs in humans such as thyroid, testicles, muscles, and renal transplants. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXCITATION-CONTRACTION COUPLING IN DYSTROPHIC MUSCLE Principal Investigator & Institution: Vergara, Julio L. Professor; Physiology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Abnormalities in the mechanisms of calcium regulation and excitation-contraction (EC) coupling that may be linked to the degeneration of skeletal muscle fibers in Becker Muscular Dystrophy (BMD) and in Duchenne Muscular Dystrophy (DMD) will be investigated using isolated muscle fibers from mdx mice. Cells from this animal model, like those of dystrophic patients, have deficiencies in the expression of the protein dystrophin. Although there is substantial biochemical evidence demonstrating the association of the dystrophin-glycoprotein complex with transmembrane- and membrane-bound muscle proteins, little is known about its specific role in the physiological aspects of a muscle fiber. The main goal of this proposal is to obtain critical experimental evidence linking the absence of dystrophin with specific alterations in the electrical propagation in the transverse tubular system and calcium signaling machinery. Several possibilities that may explain these observations will be explored experimentally. Changes in intracellular calcium concentration triggered by electrical activity of the muscle fibers will be recorded with the aid of low affinity calcium sensitive fluorescent indicators and membrane potential changes in the transverse tubules will be monitored with potentiometric indicators. The investigations will be carried out using high-resolution optical methods that permit to assess the functional state of these critical steps of the EC coupling process, not only at the cellular level, but also within sub-regions of the muscle fiber and even within a single sarcomere. We will perform these measurements across three different age groups of the mdx mouse in order to understand the progression of the disease with time. We will also test if muscle fibers from a utrophin/dystrophin-lacking double mutant mouse, which exhibits a harsher pathology (similar to DMD), show signs of more pronounced defects in EC coupling. These types of experiments are necessary to unravel the mysterious role that dystrophin may play in the normal regulation of calcium metabolism in skeletal muscle. The knowledge gained in the proposed studies will help to elucidate the functional role of dystrophin in mammalian skeletal muscle, to this date the most fundamental and elusive problem in muscular dystrophy research. The enhanced methods proposed to detect defective steps in the EC coupling mechanisms within localized submicroscopic regions of mammalian muscle fibers may become the optimal choice for the future evaluation of genetic therapeutic procedures in sub-regions of a single muscle cell. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY (FSHD) TISSUE BANK Principal Investigator & Institution: Tawil, Rabi; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001 Summary: This abstract is not available.

Studies 37


Project Title: REGULATOR

FACTOR

X--A

CARDIAC-SPECIFIC

TRANSCRIPTIONAL

Principal Investigator & Institution: Ordahl, Charles P. Professor; Anatomy; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-APR-1997; Project End 31-JAN-2006 Summary: (appended verbatim from investigator's abstract): Although skeletal muscle accounts for a large fraction of the body mass, it is one of the least regenerative of tissues. Satellite cells, which reside within the basal lamina of mature skeletal muscle fibers, are capable of mitotic expansion thereby generating new adult myoblasts to effect local repair of injured or diseased muscle. Such adult myoblasts, however, are not capable of replacing large losses of muscle tissue that occur through injury or as a consequence of chronic muscle disease, such as Duchenne's muscular dystrophy. Even after in vitro enrichment and implantation into injured muscle sites, such adult myoblasts evidence little incorporation and integration into organized muscle tissue. Ideal cells that could be used in muscle replacement therapy should be capable of: (1) large mitotic expansion potential through stem cell activity; (2) morphogenetic capacity (involving complex intra-tissue and extra-tissue interactions); (3) migratory capacity (short and long distance). At present, neither a source of such cells nor an effective muscle replacement strategy is available. These qualities are possessed by the embryonic cells that build the muscle primordia of the body. During the previous 3 years of this project we have identified, Isolated and otherwise analyzed a novel class of embryonic muscle stem cells that we name mvogenic progenitor cells (MP cells). MP cells are distinct from satellite cells in their ability to undergo migration and morphogenetic movements. MP cells are distinct from their earlier embryonic counterparts, typically referred to as "embryonic stem cells," in that they are not multipotent but are developmentally restricted to the formation of skeletal muscle tissue only. Most importantly, after transplantation from one embryo to another, MP cells act in a semiautonomous fashion to generate organized muscle tissue, even under nonpermissive conditons. Thus, MP cells retain intrinsic determined qualities that allow them to form muscle tissues even in localities that are inappropriate or even hostile. Thus, embryonic MP cells possess the qualities required for cells to be used for muscle replacement therapy. In the present proposal, we will isolate MP cells from avian embryos and analyze their cellular, tissue, and molecular properties. These studies will lead to a deeper understanding of the processes by which muscle tissue is formed in both normal and abnormal development. More important from a potential therapeutic point of view however, the properties discovered about MP cells from this study will provide a foundation for the engineering of their essential properties into other cells, such as satellite cells, for their potential use in myoblast transfer or other therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FSHD CHROMATIN

SYNDROME--DNA

REPEATS,

METHYLATION,

AND

Principal Investigator & Institution: Ehrlich, Melanie; Human Genetics Program; Tulane University of Louisiana New Orleans, LA 70118 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Fascioscapulohumeral muscular dystrophy (FSHD) is an unusual autosomal dominant syndrome caused by the loss of some copies of a


complex repeat (D4Z4) in a subtelomeric region (4q35) of one chromosome 4 homologue. The number of copies of this 3.3-kb repeat at 4q35 is polymorphic. Unaffected individuals have 11 to about 95 copies on each allelic 4q35. In contrast, more than 90% of FSHD patients have less than 10 copies at one of these allelic 4q subtelomeric regions. It has been proposed by many investigators that normally this region is heterochromatic but that when the number of tandem copies of D4Z4 is less than 10, the region loses its condensed chromatin structure, This loss of heterochromatinization, in turn, is hypothesized to induce inappropriate gene expression in the affected muscle cells. However, there have been no reports about studies of the chromatin structure in this region for normal or FSHD cells. In the planned research, immunochemical, cytochemical, and immunocytochemical methods will be used to examine whether this region is indeed heterochromatic and whether it loses the heterochromatic structure when it contains the FSHD deletion. Myoblast cultures and lymphoblastoid cell lines from normal individuals and FSHD patients will be studied. These experiments will include analysis of histone acetylation and binding of heterochromatin 1 beta protein to the D4Z4 chromatin region. Also, we will determine whether this region is late-replicating in normal cells, as is the case for heterochromatin. Consistent with the proposed heterochromatic nature of this region, it has recently been shown that this repeat is highly methylated. The preliminary study of methylation of the D4Z4 repeat will be expanded to examine whether this repeat is no longer hypermethylated in the deletion-containing chromosome 4 in FSHD cells. It has recently been shown that cells from another genetic syndrome, ICF (a DNA methyltransferasedeficiency and chromosome instability syndrome), are undermethylated in this repeat. Because abnormal hypomethylation can favor chromosome rearrangements, ICF and normal cell lines will be compared for the frequency of rearrangements in this region. The proposed research should help elucidate the molecular etiology of the enigmatic FSHD syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF THE SYNTROPHIN/DYSTROPHIN INTERACTION Principal Investigator & Institution: Froehner, Stanley C. Professor and Chair; Physiology and Biophysics; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2001; Project Start 01-APR-1995; Project End 31-AUG-2004 Summary: (from applicant's abstract) Syntrophins are modular adapter proteins, whose importance can be inferred from their association with dystrophin, the product of the Duchenne and Becker muscular dystrophy gene. In skeletal muscle, dystrophin is associated with a complex of transmembrane glycoproteins and peripheral membrane proteins that link the extracellular matrix to cytoskeletal actin. A multitude of muscle pathologies results from mutations in proteins of the dystrophin complex. All syntrophins, of which four are now known, have a characteristic domain structure: two pleckstrin homology (PH) domains, a PDZ domain and a domain unique to syntrophin (SU domain. We have shown that the tandem PH2SU domain binds to dystrophin and that syntrophin PDZ domains bind ion channels (sodium channels, certain potassium channels) and neuronal nitric oxide synthase (nNOS), thereby linking them to the dystrophin complex. In this application, we will test the hypothesis that syntrophins confer a membrane signaling function on the dystrophin complex and that the syntrophin PDZ domains are especially important. We will use biochemical and molecular biological methods to identify additional syntrophin binding proteins, including ones that associate via non-PDZ interactions. The importance of syntrophin in the association of syntrophin with agrin-induced acetylcholine receptor clusters will be

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examined in cultured myotubes. To examine the function of syntrophin interactions with skeletal muscle ion channels, we have developed genetically-altered mice lacking alpha- and b2-syntrophin. We now propose to study the effects of syntrophin deficiency on acetylcholine receptor clustering and on sodium channel distribution and physiology. Finally, the importance of syntrophins in muscle pathology will be examined. We will compare muscle abnormalities in the genetically-altered mice with mdx mouse and determine if muscle activity (in the form of exercise) exacerbates degeneration. These studies are expected to expand our understanding of the syntrophin complex as an organizing center for transmembrane signaling proteins and define the role of syntrophins in the complex. A role for syntrophin abnormalities in human muscle pathologies may also be revealed. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF THE WW DOMAIN OF DYSTROPHIN Principal Investigator & Institution: Sudol, Marius; Biochem and Molecular Biology; Mount Sinai School of Medicine of Nyu of New York University New York, NY 10029 Timing: Fiscal Year 2001; Project Start 15-AUG-2000; Project End 31-JUL-2003 Summary: (appended verbatim from investigator's abstract): Duchenne and Becker muscular dystrophies are caused by genetic lesions of the dystrophin gene. These mutations result in the production of an abnormal protein or its absence. The long term goal of our research is to fully characterize the function of dystrophin to facilitate early detection, treatment and perhaps prevention of muscular dystrophy. During the last three years, we have identified and characterized a protein module, the WW domain, which binds proline rich ligands. The WW domain is present within the carboxyterminal region of dystrophin. Dystrophin interacts with several proteins including B-dystroglycan, which spans the membrane and communicates with the extracellular matrix. The overall hypothesis to be evaluated is that the WW domain, EF hands and the ZZ domain of dystrophin mediate interaction with B-dystroglycan in vivo, and that without this interaction, a partial or complete dystrophic phenotype results at the level of organism. Our specific aims are: 1. To characterize the specificity of the interaction between the WW domain of dystrophin and the proline rich core of Bdystroglycan using site directed mutagenesis, phage displayed peptide repertoires, the SPOT technique of peptide synthesis, and immunoprecipitation. 2. To elucidate the role of the cysteine rich region of dystrophin in modulating the interaction between the WW domain, EF hands plus the Z domain of dystrophin and B-dystroglycan by mutational analysis and x-ray crystallography. 3. To provide evidence of the biological role of modular protein domains of dystrophin (the WW domain, EF hands, the Z domain) by showing that dystrophin transgenes in which any of the four domains alone or in combination with other modules is point mutated can only partially complement the mdx phenotype (muscular dystrophy in mice), in contrast to the control, a wild type transgene, which fully complements the mdx phenotype. These studies will provide insight into molecular function of dystrophin and could point towards potential therapies for Duchenne and Becker muscular dystrophies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FUNCTIONAL TETRAHYMENA

ANALYSIS

OF

CALCIUM

STORES

IN

Principal Investigator & Institution: Turkewitz, Aaron P. Associate Professor; Molecular Genetics & Cell Biol; University of Chicago 5801 S Ellis Ave Chicago, IL 60637


Timing: Fiscal Year 2001; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: Exocytosis of secretory dense-core vesicles in many cell types is triggered by a transient elevation of cytosolic calcium that is mobilized from intracellular reservoirs. The best characterized calcium reservoirs are the endoplasmic reticulum (ER) and specialized ER-like organelles. Both the structure of reservoirs as well as the organization of the proteins within them are likely to contribute to the efficiency and specificity of signaling. One indication of this is that calcium is not uniformly distributed throughout the ER, implying that sub-regions may differ in signaling potential. Calcium-rich domains may be generated by the non-random distribution of specific proteins with the membrane and lumen of these reservoirs. This has not been tested, nor are the bases for such sub-regions known. Our aim is to develop further a system in which individual proteins can be identified and analyzed both in vitro and in vivo, to address these issues. The ciliate Tetrahymena thermophila offers a host of experimental advantages for studying such mechanisms. In this proposal, we focus on an ER-like network in ciliated protists, called the alveoli, that has evolved to facilitate signaling at the cell surface. Alveolar calcium is released when cells undergo stimulation with secretagogues, and the increase in cytosolic calcium triggers exocytosis of regulated secretory vesicles. In Tetrahymena, all such vesicles are tethered at the plasma membrane and undergo synchronous membrane fusion. From the experimental perspective, this provides an ideal read-out of alveolar signaling activity. We propose to study the function of individual alveolar proteins in exocytic signaling in Tetrahymena, taking advantage of homologous recombination for in vivo analysis. To begin, we have developed a cell-free alveolar preparation that is active in calcium transport. Our first aim is to isolate biochemically the calcium buffer proteins (homologs of vertebrate calsequestrins) that reside in the alveolar lumen, and clone the corresponding genes. This will be a starting point for mutational analysis of in vivo function, using gene replacement. Other proteins that modulate calcium flux in alveoli will be identified based on direct or indirect genetic screens. The long-term aim of this work is to develop an understanding of how proteins in intracellular reservoirs contribute to calcium signaling and homeostasis. Such questions are medically important for at least two reasons. First, defects in calcium homeostasis may be a direct cause of muscle necrosis in muscular dystrophy, in which prolonged high cytosolic levels can trigger apoptosis. Secondly, a detailed understanding of alveoli in particular might be a basis for intervention against parasites belonging to the Alveolate lineage, including the organisms responsible for malaria, cryptosporodiosis, and toxoplasmosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL ANALYSIS OF LEM-DOMAIN NUCLEAR PROTEINS Principal Investigator & Institution: Wilson, Katherine L. Associate Professor; Cell Biology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2006 Summary: Emerin is a nuclear membrane protein that bines lamina filaments. Emerin mutations cause Emery-Dreifuss muscular dystrophy, affecting heart, skeletal muscle, and tendons. Emerin belongs to the conserved LEM-domain family of nuclear proteins. The LEM-domain of emerin binds BAF (barrier to autointegration factor), a conserved chromatin protein of unknown function. We propose that LEM proteins structurally link chromatin (via BAF) to the lamina, and also bind partners that mediate DNA replication or transcriptional repression. We propose to determine the essential function of three conserved LEM proteins in C.elegans: emerin, MAN1 and lem-3. In C. elelgans, all or most cells express emerin and MAN1, but the RNAi-induced loss of emerin or MAN1

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has no phenotype. However, loss of both proteins is lethal in embryos. Thus, emerin and MAN1 have essential function(s). We will test the hypothesis that all three LEM proteins bind directly to BAF and lamin, and use site-directed mutagenesis to map their binding regions. We will use RNAi to deplete each LEM protein, and pairs of LEM proteins to test for overlapping and cell-type-specific functions in vivo. By identifying and characterizing new binding partners for emerin, MAN1 and lem- 3, we will test our hypothesis that LEM proteins are directly involved in replication, transcription, or lamin dynamics. We will determine if mutant LEM proteins, whose binding activities are defined in vitro, can rescue lethality of emerin: MAN1 (RNAi) embryos. WE will screen for mutations that are synthetically lethal in an emerin null or MAN1 null background, to identify proteins that mediate the essential functions of emerin and MAN1. This work will be the first genetic analysis of the nuclear lamina. Our work will yield basic knowledge about the functions of LEM proteins, and their interactions with lamins and BAF. This work can be extended to humans to predict the molecular mechanisms of heart disease and muscular dystrophy caused by loss of emerin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTIONAL ULTRASTRUCTURE OF THE NERVOUS SYSTEM Principal Investigator & Institution: Salpeter, Edwin E. Neurobiology and Behavior; Cornell University Ithaca Office of Sponsored Programs Ithaca, NY 14853 Timing: Fiscal Year 2001; Project Start 01-JUN-1975; Project End 30-APR-2003 Summary: Verbatim from the Applicant's Abstract): The neuromuscular junction (nmj) is used as a model synapse to study an important aspect of synaptic regulation. The innervated adult nmj is a very stable synapse both morphologically and metabolically. Changes are constantly occurring during development and during aging, but its integrity is maintained to a large extent by neural innervation. A longterm aim of this proposal is to understand how the nerve maintains the structure and function of a stable nmj. One manifestation of the junctional stability is the presence of acetylcholine receptors (AChRs) at a very high density and slow degradation rate (t 1/2 about 10 days). It is well known that during development or in the reinnervation of a denervated nmj there is a replacement of a rapidly degrading, gamma subunit-containing, AChR population (Rr), by a slowly degrading epsilon subunit-containing, AChR population (Rs). The specific aims of this research are i) to test hypotheses regarding the possible stages in producing and maintaining nmj stability, ii) to establish the role played by, the AChR subunit composition, and phosphorylation of the epsilon subunit, and iii) to identify neural factors and cytoskeletal elements involved in establishing AChR stability. The role of the two AChR populations (Rr and Rs), differing in degradation properties, will be assessed. Studies will involve electron microscope autoradiography and immunocytochemistry, in vivo studies, in vitro tissue and organ culture preparations and molecular approaches. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE AND CELL THERAPY OF DUCHENNE MUSCULAR DYSTROPHY Principal Investigator & Institution: Glorioso, Joseph C. Professor and Chairman; Molecular Genetics & Biochem; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, PA 15260 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-AUG-2008


Description (provided by applicant): The proposed study represents a systematic approach to recruit subjects and develop outcome measures necessary to reach a phase I gene transfer trial in Duchenne muscular dystrophy (DMD) and in two forms of limb girdle muscular dystrophy [LGMD 2D or alpha-sarcoglycan (SG) deficiency, and LGMD 2E or beta-SG deficiency]. The prepatory stage will be carried out in years one through three of the proposal. In years four and five, Phase 1 clinical transfer trials will be done in these three forms of muscular dystrophy. The specific aims define the approach to reach the stated goals: Specific Aim 1: Identify a cohort of DMD subjects with small gene mutations to participate in Phase 1 gene transfer studies Specific Aim 2: Establish the most appropriate muscle(s) for gene transfer in a population of DMD subjects using magnetic resonance imaging (Aim 2A) and quantitative muscle strength testing (maximum voluntary isometric contraction testing or MVICT) (Aim 2B) Specific Aim 3: Identify a population of LGMD 2D (alpha-SG) and LGMD 2E (beta-SG) subjects for participation in Phase 1 gene transfer studies Specific Aim 4: Establish the most appropriate muscle(s) for gene transfer in a population of LGMD 2D and LGMD 2E subjects using magnetic resonance imaging (Aim 4A) and quantitative muscle strength testing (MVICT) (Aim 4B) Specific Aim 5: Establish appropriate delivery methods for gene transfer of adeno-associated virus (AAV) considering volume, rate, and spread of vector from the site of injection Specific Aim 6: Perform Phase 1 gene transfer trials in DMD and two forms of LGMD (2D alpha-SG) and (2E beta-SG) Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE CAUSING PAGET & LIMB-GIRDLE MUSCULAR DYSTROPHY Principal Investigator & Institution: Kimonis, Virginia E. Pediatrics; Southern Illinois University Sch of Med Box 19616, 801 Rutledge St Springfield, IL 62794 Timing: Fiscal Year 2001; Project Start 15-FEB-2001; Project End 31-AUG-2001 Summary: (Taken from the application): Limb-Girdle Muscular Dystrophy (LGMD) encompasses a clinically diverse group of disorders characterized by proximal muscle weakness first affecting the hip and shoulder girdle elevated creatinine kinase values, and non-specific changes in the muscle biopsy. In addition to clinical heterogeneity within the LGMD category, genetic heterogeneity is indicated by the existence of dominant and recessive forms. We have identified a large family with autosomal dominant LGMD and early onset Paget disease of bone (PDB). These individuals have bone pain in the hips, shoulders and back from the Paget disease. Individuals eventually become bed bound and die prematurely from progressive muscle weakness +/cardiomyopathy in their forties to sixties. Laboratory investigation indicates elevated alkaline phosphatase levels in affected individuals. CPK is normal to mildly elevated. Muscle biopsy of the oldest affected male revealed non-specific changes and vacuolated fibers. Preliminary molecular analysis excluded linkage to the known loci for the autosomal dominant and recessive forms as well as 2 loci for autosomal dominant PDB and 6 loci for cardiomyopathy. Exclusion of the candidate loci prompted a genome-wide scan of 39 family members (9 affected, 24 unaffected, 6 spouses} with 402 polymorphic microsatellite markers (Marshfield Genotyping Services). The disease locus was linked to chromosome 9p21-q21 with marker D9S301 (max LOD=3.64), thus supporting our hypothesis that this family displays a genetically distinct form of Limb-GirdleMuscular-Dystrophy associated with Paget disease of bone and cardiomyopathy. Subsequent haplotype analysis with a high density of microsatellite markers flanking D9S301 refined the disease locus to a 3.76 cM region on chromosome 9p21-13.2. This region excludes the IBM2 locus for autosomal recessive vacuolar myopathy. Two candidate genes mapped to the critical region, NDUFB6 and IL-11RA, are being

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examined for disease-associated mutations. NDUFB6 encodes a subunit of Complex I of the mitochondrial respiratory chain and the IL11RA gene product influences proliferation and differentiation of skeletogenic progenitor cells. Identification of the genes involved in the LGMDs has led to the elucidation of an entire family of proteins that function in the dystrophin-glycoprotein complex. and a basis for understanding the pathophysiology of this complex. Delineation of the genetic component responsible for the LGMD/PDB phenotype should promise similar insight and facilitate in the design of novel treatment protocols for the two disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION % MUSCLE DEVELOPMENT IN MYOTUBULAR MYOPATHY Principal Investigator & Institution: Beggs, Alan H. Associate Professor of Pediatrics; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The long term goals of this project are to understand the molecular basis for myotubular myopathy (MTM) and its defect in muscle differentiation and to use this information to develop therapies for patients with this neuromuscular disease. X-linked MTM (XLMTM), and its milder variant, centronuclear myopathy (CTNM), are a clinically and genetically heterogeneous group of disorders characterized by congenital skeletal muscle weakness that varies from rapidly fatal in the infantile period (XLMTM) to relatively nonprogressive and compatible with normal life span (CTNM). The unifying features are skeletal muscle weakness and myopathic findings on muscle biopsy, including the presence of undifferentiated-appearing small myofibers with characteristic central nuclei or a central clear zone corresponding to the internuclear space ("myotubes"). XLMTM is caused by mutations of myotubularin, a novel dual specificity protein phosphatase whose role in muscle differentiation is unknown. To better understand myotubularin function and muscle development in general, we propose to 1) characterize SP stem cells in XLMTM muscle, 2) develop gene expression profiles for XLMTM myoblasts and muscle at various stages of differentiation, and 3) use this information to identify and characterize new proteins and pathways involved in muscle differentiation. Comparison of XLMTM-associated changes in gene expression with changes in CTNM and other congenital myopathies and dystrophies will allow identification of disease-specific changes. Correlation with data on various muscular dystrophies studied by other components of this Program Project will allow determination of non-dystrophic and dystrophy-specific pathogenic pathways. Knowledge of XLMTM-specific gene expression abnormalities will help in identifying downstream consequences of myotubularin dysfunction providing potential specific targets for therapeutic interventions to treat this disease. Furthermore, better knowledge of myotubularin's role in muscle differentiation will help in identifying candidate genes for the milder related disease CTNM as well as shed light on normal muscle differentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE EXPRESSION % THERAPEUTIC APPLICATION OF MUSCLE STEM CELLS Principal Investigator & Institution: Gussoni, Emanuela; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-AUG-2006


Summary: (provided by applicant): The broad objectives of this proposal are to characterize human muscle stem cells and evaluate their potential as gene vectors for the therapy of muscle disorders. The aims of these studies are to 1) Purify muscle stem cells from human skeletal muscle, using the vital DNA dye Hoechst 33342 (H0342) and the fluorescence-activated cell sorter (FACS); 2) Use gene chip and gene array technologies to characterize the repertoire of genes expressed by human muscle stem cells and compare this to expression patterns in more differentiated myoblasts; 3) Analyze and characterize expressed genes that are specific to muscle stem cells to define possible pathways of differentiation/commitment of skeletal muscle stem cells; 4) Use the information derived from gene array technology to optimize different media compositions that will promote the propagation of human muscle stem cells in vitro; 5) Test whether human muscle stem cells can differentiate into multiple cell types in vivo by introducing them into NOD /SCID mice and assessing their ability to reach host skeletal muscles from the circulation. These studies are essential to further our basic knowledge on the existence of muscle stem cells in humans. The identification of candidate genes that are uniquely expressed by human muscle stem cells will help in understanding how muscle stem cells differ from more committed myoblasts, and start to unravel why muscle stem cells (at least from previous mouse studies) can differentiate into bone marrow. Further, exploring methods to propagate muscle stem cells will be crucial to obtain large numbers of cells for characterization experiments as well as in vivo studies. These in vivo studies are aimed to test whether human muscle stem cells can be safely used as vehicles to systemically deliver genes to skeletal muscle. The hope is to be able to extend the practical use of muscle stem cells in the development of a therapy for human muscle disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION AND DYSFERLIN-RELATED DYSTROPHIES Principal Investigator & Institution: Brown Jr, Robert H.; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Limb girdle muscular dystrophy type 2B (LGMD 2B) and Miyoshi myopathy (MM) are caused by defects in a gene that encodes a newly identified protein "dysferlin". The long-term objectives of this proposal are to characterize the biological properties of dysferlin and its role in the pathogenesis of LGMD 2B and MM and to initiate studies of cell therapy in these diseases. The specific aims are to: (1) Characterize dysferlin gene mutations and abnormalities of dysferlin protein expression in patients with MM and LGMD 2B and use this information to extend our studies of dysferlin as a novel muscle membrane protein. (2) Use conventional methods (immunoprecipitation, yeast two-hybrid analyses) to identify proteins that interact with normal and mutant dysferlin. (3) Use chip-based mRNA expression arrays to analyze dysferlin-deficient human muscle to identify changes of muscle gene expression that are either common to all dystrophies or specific to the dysferlinopathies. (4) Validate results of expression arrays and characterize genes that are unique to each of the dystrophies and begin to test new hypotheses about the molecular pathogenesis of muscle degeneration in the dysferlinopathies. (5) Analyze muscle stem cell (SP cell) populations in MM and LGMD-2B and the feasibility of SP therapy in a mouse model of dysferlin deficiency. These studies will be important because: (1) the dysferlinopathies constitute a significant proportion of all LGMD; (2) the studies in Aims 1-3 will illuminate aspects of the normal biological properties of this novel protein; (3) studies of pathological muscle in Aims 1-4 will contribute directly to

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understanding the pathogenesis of LGMD, MM and other muscular dystrophies (including facioscapulohumeral and myotonic dystrophy, included as comparative disease controls); and (4) the investigations in Aim 5 will contribute to the development of therapy for these types of muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION IN LIMB GIRDLE MUSCULAR DYSTROPHY Principal Investigator & Institution: Mcnally, Elizabeth M. Associate Professor; Medicine; University of Chicago 5801 S Ellis Ave Chicago, IL 60637 Timing: Fiscal Year 2003; Project Start 22-SEP-2003; Project End 31-AUG-2005 Summary: (provided by applicant): The muscular dystrophies are a genetically diverse group of disorders that lead to progressive muscle weakness and disability. In recent years, a number of genes have been discovered that, when mutated, lead to muscular dystrophy. In humans, mutations in the genes encoding sarcoglycan proteins produce Limb Girdle Muscular Dystrophy (LGMD). The sarcoglycan genes encode proteins each with a single transmembrane domain. Together, the sarcoglycan subunits form a subcomplex within the dystrophin glycoprotein complex (DGC). The DGC is important for stabilizing the cytoskeleton, the plasma membrane and the extracellular matrix. The loss of sarcoglycan from the plasma membrane causes degeneration to occur in both skeletal and cardiac muscle. Loss of function mutations in sarcoglycan genes causes muscle degeneration and abnormal muscle membrane permeability. Mouse models, engineered with sarcoglycan gene mutations, were found to target different aspects of sarcoglycan function (Hack et al. 1998; Hack et al. 1999; Hack et al. 2000). Mice lacking delta-sarcoglycan develop increased myocyte damage in response to the force of muscle contraction. In contrast, mice lacking gamma-sarcoglycan do not display increased myocyte damage in response to muscle contraction suggesting that gamma-sarcoglycan deficiency may cause membrane damage by a non-mechanical, or signaling, defect. Interestingly, skeletal and cardiac muscle degeneration is identical between mice lacking either gamma-sarcoglycan or delta-sarcoglycan. Therefore, these two different mouse models modify specific mechano signaling aspects of sarcoglycan function. We propose to conduct a microarray analysis of gene expression using gamma-sarcoglycan and delta-sarcoglycan mutant muscle to compare the changes in gene expression between these two forms of LGMD. The changes in gene expression in sarcoglycan mutant muscle will be compared to those found in dystrophin deficient muscle. Finally, we propose to analyze gene expression in cardiac tissue from gamma- and deltasarcoglycan mutant mice. Together, these experiments will outline the temporal profile of gene expression changes that arise in these disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENE EXPRESSION IN NORMAL & DISEASED MUSCLE DEVELOPMENT Principal Investigator & Institution: Kunkel, Louis M. Professor; Children's Hospital (Boston) Boston, MA 021155737 Timing: Fiscal Year 2001; Project Start 25-SEP-2001; Project End 31-AUG-2006 Summary: PROGRAM (provided by applicant): The last decade has witnessed remarkable progress in defining primary defects that cause inherited muscle disorders. The genetic heterogeneity of these diseases is enormous; mutations in more than 40 different genes are implicated. Many critical questions remain concerning the pathogenesis of muscle cell degeneration in these diseases and strategies for their


treatment. This Program Project will use classical methods of gene and protein analysis and state-of-the-art gene expression array technology to study these questions. The investigators in this program have contributed importantly to the muscular dystrophy field. The proposed 4 projects have unique features but overlapping concepts and methodologies. Project 1 will study the dystrophin-associated complex of proteins, emphasizing the sarcoglycans and the newly described filamin-C. Project 2 will investigate the biology of dysferlin, its potential protein partners, and how these are altered by dysferlin gene mutations. Project 3 will examine the function of myotubularin in normal muscle development and the mechanisms by which its mutations cause developmental myopathies. Project 4 will study the biological and therapeutic properties of muscle stem cells. Three Cores will provide administrative oversight and services essential to the smooth progression of this program. Core B will coordinate sample acquisition and muscle RNA preparation for each project. Core C will perform the microarray analysis of gene expression and provide expertise in bioinformatics and data interpretation. The aim is to identify patterns of gene expression that are global in all dystrophies or distinct to specific sets of dystrophies and myopathies; this will provide insight into the molecular basis of normal muscle development and its dysfunction in these disease states. The long-term goal is to use this information in conjunction with the insights from studies of stem cell biology to devise new approaches to the treatment of the muscular dystrophies and related myopathies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE THERAPY FOR DUCHENNE MUSCULAR DYSTROPHY Principal Investigator & Institution: Wolff, Jon A. Professor; Pediatrics; University of Wisconsin Madison 750 University Ave Madison, WI 53706 Timing: Fiscal Year 2001; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: (Copied from Applicant Abstract): Gene therapy promises to be a cure for the muscular dystrophies, such as Duchenne muscular dystrophy. Studies by my laboratory and others indicate that the transfer of the normal human dystrophin gene into dystrophic muscle (in the mouse model) prevents the death of the myofiber. The critical problem now is how to deliver the normal dystrophin gene to enough of the muscle cells and have it stably expressed in order to effect a cure. We have spectacular preliminary results that show that plasmid DNA can be delivered via a blood vessel into more than 10 percent of the muscle cells throughout the leg of a rat. This percentage of transfected muscle cells approaches the critical minimum percentage necessary to be curative in children with Duchenne muscular dystrophy. With this approach, multiple administrations should be possible, ensuring that a sufficient number of cells would be converted to dystrophin-positivity. Our studies also indicate that this approach should lead to stable expression of the gene. We have shown that the intravascular injection of naked plasmid DNA (pDNA) into the femoral artery of rats leads to very high foreign gene expression in skeletal muscle throughout the leg and without damaging the muscle. Previous experience with naked DNA and adenoviral vectors showed that the gene transfer efficiency decreased substantially when going from the young mouse, to adult mouse and then adult rat. The fact that we can achieve very efficient expression in an adult rat is quite encouraging. The objective of this proposal is to extend this approach to larger animals, non-human primates and the dog and its associated Duchenne model. If successful in primates and dogs, a human clinical trial in patients with Duchenne muscular dystrophy could begin in the near future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENERAL CLINICAL RESEARCH CENTER Principal Investigator & Institution: Goldsmith, Lowell A. Professor and Chair; None; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001; Project Start 01-OCT-1974; Project End 30-NOV-2000 Summary: Since 1960, the University of Rochester GCRC has fostered productive, hypothesis-driven, investigator-initiated clinical research. During the last 5 years, center investigators have published more than 200 peer- reviewed research publications focusing on such diverse areas as Infectious Diseases, Environmental Medicine, Geriatrics, Dermatology, Neuromuscular Diseases, Cardiology, Parkinson's Disease, Endocrinology and Metabolism, and Neonatology. Moreover, usage has grown and initiatives in genetics and gene therapy have been attracted to the Center. The present application contains diverse projects from medical school and nursing school faculty. The proposed projects expand ongoing studies in AIDS, aging, environmental exposures, muscular dystrophy, Amyotropic Lateral Sclerosis (ALS), Parkinson's Disease, diabetes, obesity, oncology, neonatal respiratory distress syndrome, bronchopulmonary dysplasia, and the epidemiology of pediatric infectious diseases. New initiatives include protocols to study genetics, utilize gene therapy in the treatment of ovarian cancer, and better understand posthepatectomy liver regeneration. The University of Rochester Investigators are well-funded, making the GCRC a productive and fertile research environment. This proposal also includes a major series of new educational initiatives which should particularly assist young investigators and attract new investigators. Supporting the proposed protocols are facilities that include: The Core Laboratory (RIA, HPLC, Mass Spectroscopy, and Body Composition); CDMAS, Nutrition, and a stable, well-trained, research nursing staff: In addition, the Rochester Area Pepper Center (Geriatrics), the Cancer Center, and the AIDS center will continue to integrate their programs with the GCRC to optimize realization of the full clinical research potential of the University environment. Thus, the Rochester GCRC supports a cadre of proven, productive and innovative researchers that should continue to make major contributions to our understanding of clinical disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC ANALYSIS OF SYNAPSE FORMATION AND FUNCTION Principal Investigator & Institution: Broadie, Kendal S. Professor of Biological Sciences; Biology; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2001; Project Start 01-AUG-1997; Project End 31-AUG-2002 Summary: Movement, behavior and higher brain function all depend upon the ability of neurons to communicate via specialized intercellular junctions called synapses. Many forms of neurological disease affect the synapse both in the central nervous system (CNS: e.g. Parkinson's Disease, Epilepsy) and at the neuromuscular junction (NMJ: e.g. Myasthenia and several types of Muscular Dystrophy). Moreover, synapse regeneration is central to neural repair following brain trauma (e.g. stroke) or injury. (e.g. loss of a limb). Our objective is the systematic dissection of the function and organization of individual components of the synapse. Such an analysis requires methods to identify specific synaptic proteins as well as methods to assay their function. Drosophila offers unique possibilities for a rigorous analysis of this kind: sophisticated genetic methods can be combined with refined functional and anatomical assays to study an assessable synapse, the NMJ. This proposal has two specific aims: 1) to identify new proteins involved in presynaptic function and development by performing genetic screens and, 2) to characterize the phenotype of existing mutants in order to define their role in


presynaptic mechanisms. For the first objective, screens will be conducted by identifying mutants with defective NMJs among uncoordinated lethal mutations on the third chromosome (40% of the genome). Our aim is to saturate the third chromosome for synapse dysfunction mutants, order these mutants into functional classes and initiate a molecular characterization of the isolated genes. For the second objective, we will focus on the phenotypic characterization of known synaptic mutants isolated via reverse genetic techniques. This work will include the functional and anatomical characterization of mutants in Neurexin, a Rab3A-interacting gene and double-mutant combinations of presynaptic genes. Both forward and reverse genetic approaches demand assays that measure different aspects of defective synaptic function in clear and quantifiable ways. We have developed assays to monitor the developing embryonic NMJ either in vivo or in culture using a combination of patch-clamp electrophysiology, gross morphology and ultrastructural analyses. The intention of this proposal is to bring these approaches together in order to increase substantially the number of genes known to be required at the synapse. In the long term, we intend to mutate the entire genome to identify and describe the genetic and molecular pathways directing the construction and working of the synapse. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC AND MOLECULAR ANALYSES OF MUTATIONS Principal Investigator & Institution: Brilliant, Murray H. Professor of Mammalian Genetics; Pediatrics; University of Arizona P O Box 3308 Tucson, AZ 857223308 Timing: Fiscal Year 2001; Project Start 01-JUL-1989; Project End 30-JUN-2003 Summary: (Adapted from investigator's abstract) This is a competitive renewal for an RO1 in its third funding cycle that requests five years of support to identify and analyze genes uncovered by genetic rearrangements that affect the p gene. Previous work by the applicant has defined two complementation groups -- runty/jerky/sterile (rjs) and cleft palate -- which lie proximal and distal to p, respectively. In the previous funding cycle, the applicant identified a very strong candidate for the rjs gene, demonstrated that deletion of the Gabrb3 gene was responsible for cleft palate, and, in addition, described an inversion allele, p100H, that disrupts the Sox6 gene and causes an unusual muscle disease reminiscent of Emery-Dreyfuss muscular dystrophy. The current application proposes to extend work in all three areas. The molecular pathogenesis of rjs deficiency will be investigated by further characterization of gene and protein expression, by identification of interacting proteins, and, in collaboration with others, biochemical and/or cell biologic assays of rjs domains that may function in protein ubiquitination and guanine nucleotide exchange. In addition, a loxP-flanked rjs allele will be created to investigate whether the pleiotropic phenotype caused by rjs deficiency reflects the sum of several tissue-specific defects. Preliminary studies suggest that cleft palate caused by deficiency for Gabrb3 reflects a requirement outside the central nervous system, pointing to a potentially novel role for GABA signaling during palate morphogenesis. These data will be confirmed by further studies of a Gabrb3 transgene controlled by the neuron-specific enolase promoter. In addition, the sites of Gabrb3 gene and protein expression, and GABA binding sites, will be characterized in non-neuronal tissues with special attention to the developing palate. The pathogenesis of muscle disease caused by the p100H mutation will be investigated by further characterization of a newly recognized Sox6 isoform highly expressed in muscle, by development of myoblast/myocyte cell culture systems from mutant animals, and by Sox6 gene rescue experiments in vivo and/or in vitro. In addition, differential display, cDNA subtraction,

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and/or gene expression profiling will be used to compare mutant and non-mutant tissues in an attempt to identify Sox6 targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MECHANISMS OF MUSCULAR DYSTROPHY IN MICE Principal Investigator & Institution: Cox, Gregory A. Associate Staff Scientist; Jackson Laboratory 600 Main St Bar Harbor, ME 04609 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The broad long term goals of this research are to better understand the molecular genetic mechanisms underlying neuromuscular disease using a novel mouse mutation as an experimental model. Muscular dystrophies include a diverse group of genetically heterogeneous disorders characterized by progressive muscle weakness and wasting that leads to severe disability and often premature death. There is a need to learn more about pathogenesis of the diseases and translate this knowledge into effective treatments. Toward this goal, we propose to study the mechanism of pathogenesis in the mdm mutant mouse, a novel model of progressive muscular dystrophy that functionally links the enormous Titin (Ttn) gene to the limbgirdle muscular dystrophy type 2A (LGMD2A) cysteine protease calpain 3 (Capn3). We have genetically mapped and identified the mdm mutation as a complex rearrangement that results in a small in-frame deletion within a putative CAPN3-interacting domain of TTN. The mdm mouse may also serve as a genetic model for human tibial muscular dystrophy (TMD) which maps to the TTN locus at 2q31. This is the first demonstration that mutations in Ttn are associated with muscular dystrophy and provides a novel animal model to test for functional interactions between these two disease genes. The steps we will take to elucidate the roles of titin and calpain 3 in muscle cell degeneration will be to 1) test the hypothesis that calpain 3 interactions with titin are disrupted by the mdm mutation, 2) test the alternate hypotheses that the progressive mdm muscular dystrophy is due to either reduced CAPN3 levels or aberrant activation of the CAPN3 protease, and 3) generate a Ttn-null allele by gene targeting and an allelic series of muscular dystrophy mutations at the Ttn locus using a sensitized ENU mutagenesis screen. Thus, the mdm mutant mouse provides a unique tool for understanding molecular pathways causing muscular dystrophy and may reveal entry points in which to intervene in the disease process. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC MODIFICATION OF STRIATED MUSCLES DURING AGING Principal Investigator & Institution: Metzger, Joseph M. Professor; Human Genetics; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001; Project Start 01-MAY-1998; Project End 30-APR-2003 Summary: This program project application is designed to explore mechanisms of genetic diseases that affect striated muscle, how these diseases are affected by the normal aging process, and it also seeks to develop gene therapy approaches for treating these diseases. The applicants are a diverse and broad based group of researchers with interests in ageing, muscle structure-function relationships, genetic muscle diseases, and gene therapy. The affiliated projects focus on cardiac and skeletal muscle disease and bring together the fields of gerontology, physiology, molecular biology, and genetics. Project 1 seeks to develop a new class of adenoviral vectors that lacks all viral genes and


that can transfer large genes into striated muscle of young and old animals. Project 2 aims to develop a better understanding of the role of the dystrophin associated protein complex in striated muscle, how mutations in genes that encode the proteins of this complex lead to muscular dystrophies (CDs), and how normal ageing contributes to the pathology of the MDs. Project 3 explores hypertrophic cardiomyopathies, and aims to develop adenoviral vector mediated gene transfer to the heart as a mechanism to correct inherited cardiac diseases at different stages of disease progression. These projects will be supported by four Core Laboratories. Core 1 is an administrative core to coordinate the separate projects. Core 2 is a Viral Vector Core to provide large scale growth of adenoviral vectors and assistance with their use. Core 3 is an Animal Models/Immunology Core that will house the animals for these studies, provide veterinary care and assistance with protocols, and which will also provide detailed immunological assays to study immune responses to adenoviral vector transfer. Core 45 us a Contractility Core that will measure changes in muscle contractile properties during ageing of normal and diseased muscle and following adenoviral based gene transfer to striated muscles. These projects will lead to a greater understanding of muscle diseases and ageing, and will contribute to the development of therapies for inherited diseases of skeletal and cardiac muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC REGULATION OF SKELETAL MUSCLE REPAIR Principal Investigator & Institution: Rudnicki, Michael A. Associate Professor; Ottawa Hospital Research Institute Ottawa, Timing: Fiscal Year 2001; Project Start 15-JUL-1996; Project End 31-AUG-2004 Summary: To test for a role for MyoD in muscle regeneration, we interbred MyoD mutant mice with mdx mice. The mdx mice lack dystrophin, but unlike humans do not develop extensive dystrophic damage. By contrast, mdx:MyoD-/-mice display severe dystrophic changes and cardiomyopathy that lead to premature death around one year of age. We propose to further characterize skeletal and cardiac muscle of mdx:MyoD-/mice by extensive morphometric, immunohistological, physiological, and molecular analyses. Satellite cells are a distinct lineage of myogenic cells that arise late in development. To investigate the ontogeny of satellite cells, chimeric mice will be generated using Myf-5-/-:MyoD-/- embryonic stem (ES) cells constitutively expressing lacZ. To investigate the role of the Myf-5 in satellite cell self-renewal and activation, we will investigate muscle regeneration in mice carrying MyoD or myogenin knocked into the Myf-5 allele. In addition, a Cre-inducible loss-of function mutation will be knocked into the endogenous Myf-5 allele and Cre-recombinase will be expressed from the endogenous MyoD gene, or by infection with Cre-expressing adenovirus. The ETSdomain transcription factor PEA3 is rapidly induced following muscle damage and PEA3 expression stimulates myoblast differentiation and is positively correlated with metastatic potential. We propose to characterize muscle regeneration and myoblast differentiation in PEA3-/- mice that we have generated. Many lines of evidence support the assertion that cell cycle control and myogenic factor activity is coupled via a mechanism that regulates the switch from proliferation to differentiation. We have generated null mutations in members of the retinoblastoma-family of cell cycle control genes. We will analyze muscle regeneration in vivo and myogenic cell growth and differentiation in vitro to elucidate the role of cell cycle control in myogenic stem cell function. Understanding how regulatory genes control the growth and repair of skeletal muscle is highly relevant to understanding the regenerative processes that occur in patients with various muscular dystrophy's. We believe that our proposed studies will

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provide novel insights into the biology of muscle regeneration. Potentially, such insights may lead to new modalities of therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC STUDIES OF PTS AND FAMILIES W INHERITED CARDIOVA Principal Investigator & Institution: Mcnally, Beth; University of Chicago 5801 S Ellis Ave Chicago, IL 60637 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETICS AND BIOCHEMISTRY OF A MURINE RETROPOSON Principal Investigator & Institution: Martin, Sandra L. Professor; Cellular & Structural Biology; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, CO 800450508 Timing: Fiscal Year 2001; Project Start 01-JUL-1988; Project End 30-JUN-2002 Summary: LINE-1 (long interspersed repeated sequence one, or L1) is a major dynamic force in the mammalian genome. Retrotransposition deposits the progeny of L1 throughout the genome, sometimes leading to gene disruption, modified expression of adjacent genes, and/or transduction of neighboring DNA. In addition, L1, as interspersed, repetitive DNA, provides a substrate for homologous recombination of mispaired sequences, leading to gene duplication, deletion, chromosome translocation and, potentially, exon shuffling. All of these dynamic events can lead to disease; in fact, LINE-1 insertional mutagenesis has been found to be responsible for hemophilia and muscular dystrophy, as well as breast and colon cancer in humans. Thus, it is extremely important to understand the details of the intermediates involved in retrotransposition and the mechanisms used to control their expression and movement in vivo. If the normal control mechanisms of L1 expression and retrotransposition become deranged and during development (gametogenesis or early embryogenesis) or in somatic cells in response to environmental insults, movement and rearrangement of L1 sequences could be instrumental in the generation of genetic diseases, birth defects and cancer. LINE-1 retrotransposition begins with transcription of a full-length, sense-strand L1 RNA and requires two L1-encoded polypeptides. These proteins probably also catalyze the reverse transcription and integration of SINEs (short interspersed repeated sequences) and processed pseudogenes, thereby amplifying the effects of LINE-1 in mammalian genome dynamics. Our long-range goal is to understand the retrotransposition process in detail, including the biochemical intermediates involved as well as its control in genetic and evolutionary time. Specifically, the studies proposed here are designed to: 1) Elucidate the role of the L1-encoded ORF1 protein during retrotransposition by characterizing its nucleic acid and protein- protein interaction activities in detail, as well as to test this protein for its ability to promote complementary strand annealing and strand-exchange; 2) Isolate the mouse genomic DNA progenitor of one of the promoters that was acquired by mouse LINE-1 recently in evolutionary time, and; 3) Employ our newly developed transposon tray assay to characterize the types of insertions that occur, as well as determine the frequency of endogenous L1 and L1-mediated retrotransposition events in the presence and absence of external agents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: GENTAMICIN TRIAL IN DUCHENNE AND LIMB GIRDLE DYSTROPHIES Principal Investigator & Institution: Mendell, Jerry R. Neurology; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, OH 43210 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): The study will determine if the aminoglycoside, gentamicin, has potential as a therapeutic medication for Duchenne muscular dystrophy (DMD). To fulfill this potential, long-term administration of gentamicin must be safe and improve muscle strength. Ideally, it will also increase dystrophin expression with binding at the muscle membrane. The testing paradigm will be a three-arm, sixmonth, double blind, randomized controlled trial of intravenous (IV) 7.5 mg/kg of gentamicin. Groups 1, 2, and 3 will each have 12 subjects. Group 1 will receive gentamicin every three days, while group 2 will receive drug every seven days. Group 3 subjects receive an IV placebo of 5% dextrose and saline; six subjects infused every three days and six others every seven days. In addition, gentamicin will be used in two shortterm, 14-day studies. If either of these groups responds to the 14-day administration by decreasing serum creative kinase (CK), then they become potential candidates for sixmonth administration. One group of 14-day subjects will have DMD with frameshift mutations. Despite commonly held dogma that aminoglycosides have no effect on this mutation-type, it is important to establish as effect by testing to see if CK drops. A positive outcome potentially reaches more patients, since this is the most common type of DMD gene mutation. Gentamicin will also be used to treat limb girdle muscular dystrophy subjects with stop codon mutations. If the serum CK is lowered, the potential for long-term treatment will be established for these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GORDON RESEARCH CONFERENCE ON BASEMENT MEMBRANES Principal Investigator & Institution: Kramer, James M. Professor; Gordon Research Conferences Gordon Res Ctr C/O Univ of Rhode Island Kingston, RI 02881 Timing: Fiscal Year 2002; Project Start 09-JUN-2002; Project End 31-DEC-2002 Summary: (provided by applicant): This application requests partial funding for the support of invited speakers for the 2002 Gordon Conference on Basement Membranes. This is the eleventh in a series of conferences, which have become an international forum for dissemination of new ideas and information about the structure and functions of basement membranes (BMs). These are complex, three dimensional, extracellular structures formed at epithelial mesenchymal interfaces and around mesenchymal cells, with important roles in the organization and function of most tissues and organs, e.g., blood vessels, lung, kidney, skin, peripheral nerves, and muscle. For example, basement membranes regulate the migration and organization of cells in the musculoskeletal system, as well as axons and synapses in the nervous system. Mutations in genes encoding basement membrane components result in severe inherited disorders in humans (e.g., epidermolysis bullosa of skin, congenital muscular dystrophy and associated nerve defects, Alport syndrome of kidney). Acquired defects in basement membranes also contribute to the pathogenesis of diabetic microvascular disease and serve as entry sites for infectious agents, such as leprosy, and for metastatic cancer cells. Traditionally, the conference has attracted scientists from a wide range of fields in basic research, including protein and carbohydrate structure, gene expression, cell and developmental biology, and neurobiology. In addition, it has been attended by clinicians and scientists involved in research and/or treatment of human disorders involving BM

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components of lung, blood vessels, skin, kidney, bone, muscle and immune systems. Basic studies of BM degradation and turnover are also of interest to scientists investigating dynamic processes such as angiogenesis, cancer metastasis, embryo implantation, and involution of the mammary gland and uterus. There has been substantial interest from clinicians and scientists in the pharmaceutical and biotechnology industries studying the roles of BMs in wound healing, angiogenesis, nerve regeneration, inflammation, and tissue repair. The Conference will present a diverse mixture of sessions on the basic science of basement membrane and extracellular matrix (ECM) structure, biosynthesis, assembly, turnover, and functions. Comparative studies of BM function in vertebrates and invertebrates and the roles of BM and ECM in embryonic development will also be incorporated into the program. In addition, emphasis will be given to studies on the genetic analyses of BM and ECM functions, and the generation of animal models of human BM disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION OF NATURAL MESENCHYMAL STEM CELL LIGANDS Principal Investigator & Institution: Larocca, David J.; Selective Genetics, Inc. 11588 Sorrento Valley Rd, Ste 21 San Diego, CA 921211336 Timing: Fiscal Year 2003; Project Start 10-SEP-2003; Project End 28-FEB-2004 Summary: (provided by applicant): Adult stem cells from bone marrow have the potential to provide a vast resource for regenerative medicine which would allow the replacement of injured or defective cells and tissues. While it is known that mesenchymal stem cell (MSC) populations from bone marrow have the potential to differentiate into many different cell types including bone, cartilage, fat and possibly others, there is little understanding of the molecular basis that characterizes the different progenitor cells. Also lacking is a clear understanding of the factors that regulate their growth and differentiation. The purpose of this grant proposal is to identify and characterize natural ligands from within the human genome that target cell surface receptors on mesenchymal stem cells. Phage display libraries will be constructed using novel cDNA display methods and selected on MSCs to identify natural peptide ligands that bind and internalize into MSCs. Novel selection methods will be used to select internalizing ligands with greater sensitivity than currently available techniques. Selected ligands will be characterized for specificity and function. Near term, these ligands will serve as targeting ligands for the introduction of genes and drugs into mesenchymal stem cells that would augment their use in tissue engineering and treatment of disease. Moreover, it is likely that certain ligands will be useful as biological drugs that can be used commercially to either maintain stem cell populations in an undifferentiated state, or to stimulate their differentiation to specific cell types. In the long term, an understanding of these natural ligands and their receptors on bone marrow stem cells will allow rational design of drug treatments that augment the bodies own mechanism for tissue repair due to injury (i.e. wound healing, bone and cartilage growth), or due to cell loss from diseases like diabetes, Parkinson's disease, and muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMPROVED DIAGNOSIS OF THE MUSCULAR DYSTROPHIES Principal Investigator & Institution: Hoffman, Eric P. Director; Children's Research Institute Washington, D.C., DC 20010


Timing: Fiscal Year 2001; Project Start 01-JAN-1991; Project End 30-NOV-2003 Summary: This application is the second competitive renewal of this "Improved Diagnostics of the Muscular Dystrophies" grant. During the first award, we showed that primary dystrophinopathies caused the majority of cases of muscular dystrophy, specifically about 80% of male dystrophy patients, and 10% of female dystrophy patients. During the tenure of the second award period (Dec 95-present), we begin dissecting the cause of muscular dystrophy in patients with normal dystrophin. During the last two years, we have investigated muscular dystrophies caused by alphasarcoglycan, beta-sarcoglycan, gamma-sarcoglycan, delta-sarcoglycan, merosin, integrin-alpha7, and calpain III. Despite the advances in our understanding of the molecular basis of muscular dystrophy made by our laboratory and others, we can identify the underlying molecular basis for only about 30% of autosomal recessive cases; 70% of patients with normal dystrophin can not be assigned a specific molecular diagnosis. Thus, considerable work remains to identify the many genes causing muscular dystrophy, and this is the focus of this competitive renewal. Our laboratory serves as the major referral site for molecular diagnostics of the muscular dystrophies. Through our for gratis analysis of muscle biopsies for primary dystrophinopathies, and more recently sarcoglycanopathies and merosin disorders, we have assembled what is likely the most extensive tissue-bank of frozen muscle tissue and clinical records of muscular dystrophy patients in the world. 3,049 flash-frozen muscle biopsies from muscular dystrophy patients have been received by the laboratory and fully characterized by the laboratory for dystrophin expression, histopathology, and, in hundreds of cases, gene mutations. It is these well-characterized muscle biopsy specimens which form the starting material for the molecular studies proposed in this renewal application. The goals of this current application are: 1. To continue our successful candidate gene analyses in our large cohort of muscular dystrophy patients; 2. To use the newly emerging GeneChip system (Affymetrix) to determine the changes in gene expression resulting from mutations in specific muscular dystrophy genes as a means to understanding disease progression and pathophysiology; and 3. To use the Gene Chips to identify novel muscular dystrophy genes through specific changes in gene expression. The proposed research will lead to improved understand the etiology of muscular dystrophies and improved diagnosis of these disorders. The results will enable genetic counseling of patients and their families, and should facilitate efforts directed towards rational therapies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTRACELLULAR ASSEMBLY AND TARGETING OF SIGNALING MOLECULES IN HEART FAILURE Principal Investigator & Institution: Michel, Thomas M. Chief of Cardiology; Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Timing: Fiscal Year 2001 Summary: In heart failure, the molecular regulation of intracellular and intercellular myocardial signaling pathways is often profoundly perturbed. Many signaling proteins in cardiac myocytes, including G proteins, G protein- coupled receptors, calciumregulatory proteins, and nitric oxide synthase- are localized in sarcolemmal caveolae. Cardiac myocyte caveolae represent highly specialized invaginations of the sarcolemma, and form the T-tubular system that organizes and regulates sarcomere calcium delivery. Myocyte caveolae contain the protein caveolin-3, a transmembrane protein that serves a scaffold for the localization of many signaling proteins. During the initial funding period of this SCOR, we discovered that the endothelial isoform of nitric oxide synthase

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(eNOS) is expressed in cardiac myocytes and that its activity is regulated by its interactions with caveolin-3. The central hypothesis to be tested in these studies is that nitric oxide synthase and other key caveolae-targeted signaling proteins are aberrantly regulated in heart failure. In Aim 1, we will determine the composition the composition and regulation of cardiac myocyte caveolae in normal and failing hearts, and characterize the signaling proteins present in cardiac myocyte caveolae following receptor activation in vivo and in vitro. We will perform cellular imaging of caveolaetargeted signaling proteins using confocal laser microscopy, and identify the intracellular sites of NO synthesis in cardiac myocytes using the newly developed fluorescent dye, diaminofluorescein. Both eNOS and iNOS will be studied in this context, analysis of iNOS localization may provide new information on the role of NO in myocardial depression in systemic sepsis. These cellular imaging studies of caveolae constituents will be analyzed in the murine heart failure models being studied by other SCOR investigators. In Aim 2, we will conduct fluorescence resonance energy transfer experiments to explore interactions between cardiac myocyte-derived NO, caveolin and Ca++-binding regulatory proteins in T-tubules. In Aim 3, we will explore the role of caveolin-3 in regulation of NO-dependent signaling pathways in the myocardium; these studies may yield insights into the pathophysiology of cardiomyopathies associated with muscular dystrophy syndromes. In Aim 4, we will characterize the electrophysiological phenotype of eNOS/null mice using programmed electrical stimulation and drug infusions, as well as ambulatory EGG monitoring in eNOS/null mice, including heart rate variability analysis. Since we have shown that eNOS importantly modulates the autonomic control of myocyte beating rate in vitro, the in vivo studies in Aim 4 may provide new insights into the molecular mechanisms of sudden cardiac death in heart failure. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INVESTIGATION OF A DYSTROGLYCAN COMPLEX IN EPIDERMIS Principal Investigator & Institution: Santas, Amy J.; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, WA 98109 Timing: Fiscal Year 2003; Project Start 01-DEC-2003 Summary: (provided by applicant): The main objective of this proposal is to compare two epidermal cell adhesion complexes, a dystroglycan-containing complex (DGC) and the hemidesmosomes. Hemidesmosomes and the DGC are transmembrane receptor complexes that serve to connect the extracellular matrix and the cytoskeleton and are essential to maintain integrity of epidermis and muscle, respectively Severe blistering results from genetic defects in hemidesmosome components while muscular dystrophy develops from defects in DGC components In our preliminary studies, two components of DGC (utrophin & Beta-dystroglycan) were identified in epidermal tissue and uncultured primary keratinocytes Upon culturing, neither components of DGC nor mature hemidesmosomes were detectable This proposal will delineate the composition of the epidermal DGC and its physical and functional relationship with hemidesmosomes in epidermis and in an in vitro system to be developed. Ultrastructural association of DGC and hemidesmosomes will be examined using immunoelectron microscopy while functional interrelatedness will be examined by staining for DGC in tissues that do not form hemidesmosomes Loss of hemidesmosomes or decrease in dystroglycan expression directly correlates with poor prognosis in epithelial cell based cancers The long term goal of this research is to identify the role of the complex(es) in cancer as to better understand the progression and targets of these cancers.



Project Title: ION CHANNELS AND CHEMICALS CONTROLLING SYNAPSE STABILITY Principal Investigator & Institution: Mcardle, Joseph J. Professor; Pharmacology and Physiology; Univ of Med/Dent Nj Newark Newark, NJ 07103 Timing: Fiscal Year 2003; Project Start 01-FEB-2003; Project End 31-JAN-2007 Summary: (provided by applicant): Synapses are the major locus of information transfer within our brain as well as the target of numerous pathologies which can afflict humans from development in utero to death. Therefore, major research effort is given to understanding synapse formation and stabilization throughout life. The scientific literature concerning synapses is rich with discovery of fundamental principles derived from study of the neuromuscular junction (NMJ). In particular, proteins responsible for NMJ function, formation, and stability are relatively well understood. Nevertheless, fundamental questions remain concerning interactions between these proteins. An important experimental model suggests that heterogeneous activity of AChRs influences stability of the adult NMJ. This proposal modifies and extends that model to the developing NMJ where co-expression of immature gamma and mature epsilon AChRs during the critical phase of NMJ maturation produces heterogeneity of end-plate activity. Our model suggests that end-plate areas rich in epsilon AChR mediate Ca 2+ influx which activates co-localized nitric oxide synthase (nNOS). The nitric oxide (NO) produced diffuses to nerve terminals competing for the motor end-plate. New preliminary data suggest that NO enhances Ca2+ currents and transmitter release at adult motor nerve terminals. Thus, developing nerve terminals activating end-plate loci containing the epsilon AChR may be functionally enhanced and nurtured via NO activation of presynaptic guanylyl cyclase. In contrast, NO may repress function and stability of competing nerve terminals activating epsilon AChR poor end-plate foci. The mouse Triangularis sterni (TS) preparation facilitates exact testing of our model. Our preliminary data show that the TS preparation isolated from neonatal mice allows simultaneous recording of nerve terminal currents and post-synaptic events at endplates receiving innervation from terminals originating in distinct nerve trunks. This allows unprecedented study of the function of, and NO-mediated cross talk between, mammalian nerve terminals competing for a postsynaptic target. The availability of epsilon subunit and nNOS knock out mice, as well as the epsilon AChR selective ligand Waglerin- 1 further strengthen experiments proposed to test our model. Additional novel preliminary data suggest that insulin, an activator of the neuronal K-ATP channel, suppresses quantal release of Ach at the adult NMJ. Therefore, a second goal of this proposal is to discover if insulin, as well as glucose, effects the function, and eventual stability, of nerve terminals competing at the developing NMJ. This will be explored in a non-obese mouse model of type I diabetes. Overall, this research is clinically relevant since NO signaling cascades are significantly altered in Duchenne muscular dystrophy as well as animal models of stroke. In addition, altered function of the epsilon AChR is responsible for NMJ pathology associated with slow channel congenital myasthenic syndrome. The proposed evaluation of insulin effects is novel and will enhance understanding of the neurologic consequence of adult and juvenile forms of diabetes. The knowledge gained from this research will enlighten future molecular approaches to treating pathologies which afflict children and adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LAMININ ALPHA 2 IN TISSUE REGENERATION Principal Investigator & Institution: Engvall, Eva S. Associate Scientific Director; Burnham Institute 10901 N Torrey Pines Rd San Diego, CA 92037 Timing: Fiscal Year 2001; Project Start 01-MAR-1996; Project End 28-FEB-2005 Summary: (Adapted from applicant's abstract) Tissue regeneration and repair are critical to longevity. Insufficient regeneration of muscle and nerve is a significant cause of morbidity in patients with muscular dystrophy and other muscle and nerve diseases and in the aging individual. The laminin subunit a2 is prominently expressed in striated muscle and peripheral nerve, and mutations in the lama2 gene cause a severe form of muscular dystrophy in humans (merosin-deficient congenital muscular dystrophy, MCMD) and mice. A mouse model for human MCMD was generated by disrupting the lama2 gene with the lacZ reporter gene. Homozygous mutant mice develop muscular dystrophy and peripheral neuropathy after birth. Absence of laminin a2 does not significantly affect myogenesis, but the differentiated laminin a2-deficient muscle are highly susceptible to injury upon contraction. Most important, in contrast to the apparent normal development, regeneration is severely compromised in the absence of laminin a2. It is proposed to use in vivo and in vitro models to analyze development and regeneration of skeletal muscle and peripheral nerve to determine which steps in the regeneration process are dependent on laminin a2. The regeneration-promoting effects of laminin a2 will be analyzed in transgenic mice with tissue-specific overexpression of a human LAMA2 transgene. To analyze the molecular pathways responsible for maturation and survival of skeletal muscle and Schwann cells, integrin and dystroglycan signaling pathways will be characterized by using the yeast 2-hybrid screening and affinity chromatography in combination with peptide mass mapping. The proposed research will result in new knowledge regarding important molecular mechanisms of muscle and nerve function and may help in devising new strategies for treatment of degenerative diseases of muscle and nerve based on promoting regeneration. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LAMININ INDUCED MEMBRANE COMPLEXES IN MUSCLE AND NERVE Principal Investigator & Institution: Yurchenco, Peter D. Professor; Pathology and Lab Medicine; Univ of Med/Dent Nj-R W Johnson Med Sch Robert Wood Johnson Medical Sch Piscataway, NJ 08854 Timing: Fiscal Year 2001; Project Start 01-APR-1999; Project End 31-MAR-2004 Summary: Null and domain-activating mutations of the basement membrane laminin alpha2 (merosin) subunit are reported to cause human and murine congenital muscular dystrophies and peripheral nerve defects. Our laboratory is studying the inductive role of laminins on myotubes and Schwann cells, and preliminary data reveal that alpha2laminin and its alpha1-laminin homologue binding to myotube cell surfaces through laminin G protein-specific integrin and alpha-dystroglycan receptors. These cruciform laminins self-assemble into polymers through their short arms, cluster the two receptors into polygonal complexes through their anchored long arm, and induce the formation of a vinculin-rich cortical cytoskeletal lattice that mirrors the organization of laminin and its receptors. We also have evidence that alpha2-laminin bearing the dy/2.1 dystrophic deletion is defective in its ability to self-assemble, to aggregate its receptors, and to assemble this cortical architecture. Based on these and other data, our working hypothesis is that laminin-2 plays a major role in driving the assembly of the myotube


and Schwann cell cytoskeleton, a process mediated by its ability to bind to the cell surface, to polymerize, and to activate and reorganize its cognate receptors. This receptor and cytoskeleton reorganization, resulting from a dynamic integration of laminin activities, may be important for the development, maintenance and stabilization of muscle and nerve sheaths. Furthermore, a loss of one or more of these functions may cause muscular dystrophies with neuropathies. We propose to explore this concept in the following specific aims: I. Laminin-Myotube and Laminin-Schwann Cell interactions: We will study the composition, architecture, and sequential assembly of laminin-induced receptor-cytoskeletal complexes in normal and receptor-deficient myotubes and Schwann cells. II. Structure and function of Recombinant alpha2Laminins Bearing Dystrophic Mutations: We will prepare and evaluate the structure and function of recombinant laminins bearing dystrophic alpha2-subunit mutations with respect to their structure, domain stability, self-assembly, and receptor activities. III. Dystrophic Recombinant Laminin Induction of Receptor-Cytoskeletal Complexes: We plan to study engineered laminins with respect to their ability to induce membrane cytoskeletal networks in myotubes and Schwann cells. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LAMININ RECEPTORS AND SIGNALS IN SCHWANN CELLS Principal Investigator & Institution: Feltri, Maria L.; Istituto Scientifico San Raffaele Via Olgettina 60 Milano, Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): Laminin is important for peripheral nerve development and myelination. Laminin mutants cause a dysmyelinating neuropathy in man (congenital muscular dystrophy, CMD) and mouse (dystrophic, dy) that manifests both impaired Schwann cell-axon interactions and altered myelination. The molecules that transduce laminin effects in Schwann cells, and the pathomechanisms of laminin mutants remain largely unknown. We have identified several laminin receptors in myelin-forming Schwann cells and shown that they are differentially expressed across peripheral nerve development, suggesting that they subserve differential roles. Our preliminary genetic analysis confirms this notion: Beta1integrin is required for establishing proper Schwann cell-axon relationships prior to birth, whereas dystroglycan is necessary for normal myelination after birth. The Beta1and dystroglycan-null morphological phenotypes suggest that these receptors normally link laminin to cytoskeletal rearrangements in Schwann cells. The overall goal of this proposal is to expand what is known of the molecular basis of laminin-cytoskeletal linkage in Schwann cells. We have produced or collected an unique group of conditional alleles and Cre transgenes that will allow us to disrupt singly or multiply all known major laminin receptors in Schwann cells of transgenic mice. Furthermore, imaging and biochemical analysis of Beta1integrin-null Schwann cells will elucidate how Beta1 directs cytoskeletal rearrangements. Proteomic analysis of Beta1integrin-null Schwann cell/neuron explants will identify candidate signal molecules that link laminin to the cytoskeletal alterations required for axonal interactions. This comprehensive approach will establish the role of the different laminin receptors in peripheral nerve, thereby clarifying the pathogenesis of CMD and dy mutations. The information produced by these experiments will collectively form a basis for developing treatment strategies of CMD and other hereditary neuropathies, and to promote nerve regeneration and remyelination in all neuropathies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIMB GIRDLE MUSCULAR DYSTROPHY GENE THERAPY Principal Investigator & Institution: Campbell, Kevin P.; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2001 Summary: Autosomal recessive limb-girdle muscular dystrophy (AR-LGMD) refers to a number of genetically and clinically heterogenous neuromuscular disorders that affect mainly skeletal muscle. Over the last few years, it has become clear that a number of genes encoding protein components of the sarcoglycan complex are responsible for several forms of AR-LGMDs. The sarcoglycans are expressed at the sarcolemma of muscle fibers and, along with other proteins, constitute the dystrophin-glycoprotein complex (DGC). These proteins are believed to play a role in maintaining the normal architecture of the muscle cell membrane by constituting a link between the subsarcolemmal cytoskeleton and the extracellular matrix. In particular, we have shown that alpha-sarcoglycan, a 50 kDa component of the DGC, is a deficient in skeletal muscle from patients having limb- girdle muscular dystrophy type 2D, and that the expression of all the other sarcoglycan proteins is also strongly reduced in muscle from these patients. Although these findings constitute great progress in our understanding of the genetic basis for AR-LGMDs, there have been no improvements in the treatment of these invalidating diseases. The long-term goal of this research proposal is the development of a gene transfer strategy for AR-LGMDs. We recently generated an animal model for LGMD2D by disrupting the alpha-sarcoglycan gene in mice and preliminary analyses of homozygous mutant mice indicate that their skeletal muscle displays a dystrophic phenotype, as expected, thus providing a valuable animal mode for LGMD2D. The overall objective of this pilot project is to develop a virally-mediated gene transfer of alpha-sarcoglycan and to investigate its therapeutic potential in alphasarcoglycan deficient mice. Our first aim will be the construction of recombinant adenovirus and adeno-associated virus vectors containing the human alpha-sarcoglycan deficient mice. Our first aim will be the construction of recombinant adenovirus and adeno-associated virus vectors containing the human alpha- sarcoglycan cDNA. These vectors will first be tested for their ability to induce expression of alpha-sarcoglycan, both in cultured myoblasts and myotubes. We will then proceed to in vivo experiments designed to test the following hypotheses: i) direct intra-muscular injections of adenoviral- based vectors containing the alpha-sarcoglycan cDNA will efficiently allow expression of the protein and restoration of the DGC in of skeletal muscle of mutant mice (Aim 2) and ii) gene transfer of alpha-sarcoglycan will support functional restoration of muscle fibers in these mice (Aim 3). Overall, the experiments outlined in our proposal will yield new information about alpha-sarcoglycan and the potential for virally-mediated alpha-sarcoglycan gene transfer in mutant mice. In addition, our findings should constitute a foundation for future investigations directed towards developing gene therapy for LGMD2D patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LLAMA-DERIVED PHAGE DISPLAY ANTIBODY ARRAYS FOR FSHD Principal Investigator & Institution: Van Der Maarel, Silvere M.; Leiden University 46 Stationsweg Leiden, Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): The aim of this project is to gain insight in the cellular and molecular processes leading to dysfunction of the neuromuscular system in


FSHD patients by large scale analysis of protein homeostasis in tissues and cell lines of patients and controls. In the past few years, projects have been launched to study deregulation of biological pathways in FSHD on RNA level. These strategies include differential display and RNA profiling experiments on commercial and custom made DNA chips and arrays. Despite their limitations, DNA arrays are now one of the most commonly used and successful methods to determine the molecular and cellular aspects of many acquired and genetic diseases. It is anticipated that also for FSHD, this approach will provide a valuable contribution in understanding its pathology. Nevertheless, protein levels, including the level of modified proteins and the composition of protein complexes are of an order of importance larger to understand FSHD pathophysiology. Consequently there is a need for protein arrays. The llama antibody technology provides a unique opportunity to develop protein arrays. The power of the llama system for this purpose is that this animal makes single (heavy) chain antibodies. Using the genetic information for this single-chain repertoire for the construction of phage-display antibody libraries abolishes the need to combine heavyand light-chains, one of the major drawbacks of conventional phage-display libraries. Moreover, these single-chain antibodies tend to have a very high affinity and stability. It has already been demonstrated that large naive and directed libraries of antibodies can be generated. Experience in cloning, production and isolation of these llama antibodies is available. We propose to generate muscle-specific antibody arrays derived from Llama single-chain phage-display clones. To this end, a Llama will be immunized with human muscle protein homogenates, and after peak response, a phage display library will be constructed. Antibody clones will be selected with a variety of selection procedures (e.g. with recombinant proteins or with muscle homogenates from different species) and arrayed on glass slides. Well characterized single chain antibody arrays will be used to study FSHD pathophysiology on fluorescently labeled protein homogenates of tissues and cell cultures of patients and controls. Evidently, these antibodies can also be used individually for specific immunohistochemical and immunocytochemical studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MANIPULATION OF PRENATAL STEM CELL TRANSPLANT BIOLOGY Principal Investigator & Institution: Merchant, Aziz M.; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2005 Summary: (provided by applicant): Duchenne's muscular dystrophy results from a genetic deletion that creates dysfunctional dystrophin protein resulting in ongoing muscle damage Injured muscle is replaced with more dysfunctional muscle from defective satellite cells which represent the muscle stem cell pool. In utero mesenchymal stem cell transplantation has been shown to result in site specific differentiation and long-term engraftment of skeletal and cardiomyocytes, however the efficiency of engraftment is very low. The rationale of this proposal is that more efficient stem cell engraftment could be obtained by manipulation of embryologic signals involved in homing and migration of myogenic progenitor cells. These signals include transcription factors, such as Pax7, which have been shown to orchestrate specification of muscle progenitors towards satellite cells and other downstream regulatory factors. My research project will involve two specific aims. Specific aim 1 will assess the molecular and biological effects of forced Pax7 expression in a defined population of multipotent adult progenitor cells (MAPC) with the focus on events involved in myogenic

Studies 61

differentiation. The second specific aim will assess the effect of forced Pax7 expression on homing, engraftment, and differentiation of MAPC after systemic administration in a murine model of in utero stem cell transplantation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISM OF CARDIOMYOPATHY IN SARCOGLYCAN DEFICIENCY Principal Investigator & Institution: Heydemann, Ahlke; Medicine; University of Chicago 5801 S Ellis Ave Chicago, IL 60637 Timing: Fiscal Year 2001; Project Start 15-SEP-2001 Summary: Mutations in sarcoglycan, a dystrophin-associated protein complex, cause cardiomyopathy and muscular dystrophy in humans. Through gene targeting, we have generated mice lacking different sarcoglycan subunits to understand better the mechanism by which the loss of these proteins produces membrane instability and cardiac muscle damage. Gamma-sarcoglycan and delta-sarcoglycan are highly related 35 KD, transmembrane proteins. Mice lacking either these sarcoglycans develop cardiomyopathy and show membrane defects characteristic of those seen in humans with mutations in these genes. Gamma-sarcoglycan is expressed exlusively in cardiac and skeletal muscle, yet mice lacking gamma-sarcoglycan appear to have smooth muscle vascular alterations similar to those seen in mice lacking delta-sarcoglycan. Thus, such defects may be a secondary consequence of the primary loss of sarcoglycan in the cariomyocyte. To investigate this, we will compare mice lacking gamma- or deltasarcoglycan. We will rescue smooth muscle expression of delta-sarcoglycan. We will investigate the role of nitric oxide synthase since unopposed vasoconstriction has been identified as a mediator of abnormal vascular tone in the absence of dystrophin. Lastly, we will study whether cardiomyocyte degeneration produces vascular changes by studying other models of cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MECHANISMS DIFFERENTIATION

OF

TGF-B

REGULATION

OF

MUSCLE

Principal Investigator & Institution: Liu, Dong; Growth and Development; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2002; Project Start 01-MAR-2002 Summary: (provided by applicant): The overall goal in this proposal is to establish physiologically relevant models about how TGF-Beta signaling through the Smad pathway regulates the terminal differentiation of skeletal muscle cells. The first part of the project aims to characterize the mechanism(s) through which TGF-Beta-activated Smads repress the function of MyoD family of myogenic bHLH transcription factors and inhibit muscle differentiation. Specifically, these experiments will extend our initial finding about a role for Smad3 in repression of muscle-specific transcription by determining the underlying mechanism(s), as well as the contribution of each potential mechanism to the antagonistic effect of TGF-beta during myogenesis. The second aim of this proposal is to evaluate the physical and functional interaction between Smads and MEF2 family of transcription factors, and elucidate the impact of such interaction on myogenic differentiation. Finally, since it is important to extend the role of Smad signaling in myogenesis in vivo, we will determine the consequence of altered Smad3 function to the differentiation of myoblast cells injected to normal skeletal muscle tissues and myofiber regeneration following injury and in muscle dystrophy mouse models.


Our study on the myogenic regulatory function of Smads will provide new insights on how TGF-beta and peptide growth factors in general, regulate mesenchymal cell differentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT

PATIENT

ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Escolar, Diana M. Associate Professor of Neurology & Pedia; Children's Research Institute Washington, D.C., DC 20010 Timing: Fiscal Year 2001; Project Start 10-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The applicant is a neurologist and has extensive clinical experience in pediatric and adult neuromuscular diseases. This award will allow her to obtain the training and mentoring to become an independent clinical investigator focusing on neuromuscular disorders. The educational plan includes didactic courses covering epidemiology, statistics, clinical trial design and health policies. DMD is a relatively common fatal genetic disease in children, with equal incidence throughout the world. The goal of this research is to conduct therapeutic human clinical trials with chemicals shown to improve muscle strength in the mdx. The aims of the proposed research plan are: 1) to conduct a double-blind, placebo-controlled, three-arm clinical trial of creatine and L-glutamine in patients with DMD and to assess the effect of these compounds on muscle strength as measured by manual muscle testing (MMT), quantitative muscle testing (QMT) and other functional measurements. Aim 2 is to conduct a double-blind, placebo- controlled clinical trial of coenzyme Q10 (CoQ10) in patients with DMD to assess its effects on: a) muscle strength, measured by QMT, compound Medical Research Council (MRC) score and functional measures; b) exercise capacity, to be measured by a fatigability protocol; and c) quality of life, to be measures by the Child Health Questionnaire. Aim 3 is to validate the specificity of the pediatric QMT system measuring maximal voluntary isometric contraction sequentially in children with DMD. The studies will be conducted at Pediatric Clinical Research Center (PCRC) at the Children's National Medical Center (CNMC), satellite to Georgetown General Clinical Research Center (GCRC). Three cores of the PCRC will be involved: the Biostatistics Core, the Genetics Core Laboratory and the Bioanalytical Core Laboratory. In addition, to increase the statistical power of this study, the applicant has assembled an international collaborative group that will conduct identical protocols and submit the data to the study center at CNMC. Future studies will test several other drugs with potential to improve muscle strength in DMD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR ANALYSIS OF THE YEAST ACTIN CYTOSKELETON Principal Investigator & Institution: Drubin, David G. Professor; Molecular and Cell Biology; University of California Berkeley Berkeley, CA 94720 Timing: Fiscal Year 2001; Project Start 01-JUL-1989; Project End 30-JUN-2002 Summary: Biochemical and genetic approaches will be used to study actin assembly in yeast. Principles established are likely to apply to more complex eukaryotes where actin dynamics underlie diverse cellular processes and where defective cytoskeleton function contributes to conditions such as muscular dystrophy, certain hereditary anemias, and cancer. The following aims will be pursued: (1) Actin nucleotide-binding pocket mutant. To test physiological importance of actin ATP hydrolysis and Pi release, and to genetically identify regulators of filament stability, we will take advantage of a unique

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actin mutant. The V159N mutation uncouples the actin nucleotide cycle from filament destabilization. Specifically, we will test the role of rapid actin filament turnover in pheromone-induced cellular morphogenesis and cortical actin patch motility, and will use the V159N mutant to genetically identify regulators of actin dynamics. (2) Biochemical and structure-function analysis of the cofilin-actin interaction. Our isolation of yeast cofilin, elucidation of its three dimensional molecular structure, and demonstration that it promotes actin filament disassembly in vivo, provide a strong foundation for further studies of this important and ubiquitous protein. The molecular models of yeast cofilin and actin filaments will now be docked, providing novel insights into the mechanism of cofilin-promoted filament disassembly. To more fully elucidate steps regulating the assembly/disassembly cycle, we will identify factors which stimulate formation of ATP-actin monomers from ADP-actin:cofilin complexes formed during disassembly. (3) Genetic analysis of cofilin regulation and regulation of actin filament stability. In response to regulatory signals, changes in actin assembly typically occur on time scales that mandate regulation by second messengers and posttranslational modification. Since genetic approaches provide powerful avenues to elucidation of regulatory pathways, proteins which regulate cofilin will be identified by genetic suppression. These studies are important for determining how cells trigger rapid cytoskeletal rearrangements required for diverse processes including morphogenesis and cytokinesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR CELL BIOLOGY GORDON CONFERENCE Principal Investigator & Institution: Walter, Peter; Professor; Gordon Research Conferences Gordon Res Ctr C/O Univ of Rhode Island Kingston, RI 02881 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2002 Summary: A basic knowledge of cell biology is a requisite for understanding the defects in cell function that cause human diseases, including many cancers, muscular dystrophy, neurodegenerative disorders, blistering skin diseases, and cardiovascular disease. In recent years, cell biologists have played an increasing role in elucidating the mechanisms underlying genetic disorders, and understanding the biology of eukaryotic cells now becomes key in the quest to develop new and improved methods for the prevention, diagnosis and therapy of human disease. The 2001 Gordon Conference on Molecular Cell Biology focuses on recent developments in cell biology that were instrumental in determining genetic bases of diseases and now provide insights into methods for diagnosis and prevention of disease. The key features of this meeting are its diversity and scientific excellence. Emphasis is on cutting-edge science leading to new scientific principles and novel approaches to cell biology. A wide range of topics is represented, including cell cycle, cell polarity and movement, cell adhesion, genetic diseases, cell biology and disease. The organizers are Peter Walter and Ira Herskowitz (both at University of California, San Francisco). The meeting will bring together and foster discussion among world- renowned cell biologists. Participants will present their most recent and exciting results involving a number of model systems and using a variety of novel technical approaches. Nine sessions, each involving four major talks, are planned. Time will be reserved at the end of each session for short oral presentations on breaking developments. Thirty-five speakers, all leaders in their fields, have agreed to attend; approximately 30% of these are women. One more person will be invited. Daily poster sessions will enable all participants to present and discuss their most recent results. There will be abundant opportunities for informal discussion among speakers,


postdoctoral fellows, and graduate students. This grant requests partial support for this exciting meeting. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETIC CHARACTERIZATION OF MYOTONIC DYSTROPHY Principal Investigator & Institution: Krahe, Ralf; Medical Microbiol & Immunology; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, OH 43210 Timing: Fiscal Year 2001; Project Start 24-SEP-2001; Project End 31-DEC-2001 Summary: (provided by applicant): The myotonic dystrophies (DM) are now collectively recognized as a clinically and genetically heterogeneous group of neuromuscular disorders, characterized by autosomal dominant inheritance, muscular dystrophy, myotonia, and multi-system involvement. Recent work by others and us indicates at least two more DM loci in addition to DM1, the (CTG)n expansion in chromosome 19q13.3. Multiple families with clinically variable presentation from predominantly distal to exclusively proximal muscle involvement show linkage to a locus in 3q21, designated DM2. However, several families with similar presentations have been excluded from this region. Thus, there is at least a third DM locus (DM3), which has yet to be mapped. The long-term goal of this proposal is the identification of DM2 in the families mapping to 3q21, and the mapping and cloning of the remaining gene(s) in the DM2-unlinked families. The characterization of the underlying mutations will be the basis for phenotype/genotype correlations. Three specific aims are proposed: (1) to clone and characterize DM2 in 3q21; (2) to clone and characterize the gene(s) in DM2unlinked/DM3 families, and (3) to globally expression profile DM muscle with DNA microarrays. Collaborating with clinical groups from the USA and Europe, we have ascertained 57 families with clinically similar phenotypes, which are negative for the DM1 (CTG)n expansion or any of the other known myotonia loci. Ten of 21 families suitable for linkage analysis show linkage to 3q21, while 11 are unlinked. We have substantially narrowed the DM2 critical region, generated a physical transcript map and started to examine functional-positional candidate genes, using various mutation detection assays. For DM3 we propose the same strategy of positional cloning that has proved successful for DM2. Genome-wide expression profiling of DM muscle will identify dysregulated genes and provide valuable functional clues about potential candidate genes and complex cellular candidate pathways, the overall pathophysiology of DM, and potential molecular therapeutic targets. The identification of these novel genes and the characterization of their mutations and pathophysiological role(s) are the first step in developing potential therapies for patients suffering from these inherited myotonic dystrophies. Moreover, as the cellular pathologies among the different myotonic dystrophies show considerable overlap, the identification of the genes underlying DM2 and DM3 and their corresponding expression profiles may also provide valuable insights into the pathology of DM1, which continues to elude researchers. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MODELS

MOLECULAR

GENETICS

OF

MUSCULAR/NEUROSENSORY

Principal Investigator & Institution: Nishina, Patsy M. Staff Scientist; Jackson Laboratory 600 Main St Bar Harbor, ME 04609 Timing: Fiscal Year 2002; Project Start 15-APR-2002; Project End 31-MAR-2006

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Summary: (provided by applicant): We have recently identified a spontaneous mouse mutant, veils (vis), that has retinal vasculopathy, hearing loss and progressive muscle wasting, phenotypes reported for many human diseases, such as Coat's disease, syndromic and non-syndromic congenital hearing loss, and muscular dystrophy, respectively. We have mapped veils to a 0.19+/-0.13 cM interval on mouse Chr. 8 in a 1,072 meiotic recombinant cross and established the physical contig of the critical region. Portions of human Chrs. 2, 4q, 8, 13, 17, 18, l9p and 22 map to this region, the breakpoints of which have yet to be refined. Interestingly, veils has many, if not all of the phenotypes reported for the disease fascioscapulohumeral muscular dystrophy la (FSHD), the third most prevalent muscular dystrophy that affects 1/20,000 and maps to human Chr. 4q35. Also, a neuromyopathy associated with a highly variable age-of-onset maps to Chr. l9pl3. Veils is a potential genetic and/or phenotypic model for these diseases. The veils mouse is also unique in that it shows retinal lamination abnormalities, a phenotype that has not previously been reported in the literature. In order to understand the biological mechanisms that underlie the disease processes and identify the biochemical pathways that are affected in different tissues, we will: (a) positionally clone the veils gene and identify the mutation in the second allele myd and test the hypothesis that the phenotypic differences between v/s and myd are explained by allelic heterogeneity; (b) begin to identify genes in the genetic background that can significantly alter the disease phenotypes of vis/vis mice; and (c) test the hypothesis that the observed phenotypes are the result of developmental defects rather than degenerative processes. Identification of disease causing genes and animal models is extremely important. Many diseases in humans, especially those involving the eye, if identified early enough, can be treated to attenuate the disease process. If no treatment is currently available, knowing the molecular basis of the disease may provide insights to new treatment regimens and the models can then be used to test those therapeutics. Finally, knowledge of the disease causing genes may lead to an understanding of pathways that are critical in maintaining normal function and physiology of the organism and perhaps, may identify therapeutic targets for prevention of muscle wasting, and vision or hearing loss. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR GENETICS OF PRONUCLEAR FUNCTIONS IN DROSPHILA Principal Investigator & Institution: Wolfner, Mariana F. Professor; Molecular Biology and Genetics; Cornell University Ithaca Office of Sponsored Programs Ithaca, NY 14853 Timing: Fiscal Year 2002; Project Start 01-MAY-1991; Project End 31-AUG-2006 Summary: (provided by applicant): To initiate development, a newly fertilized egg must generate pronuclei that can combine to create a zygotic genome capable of initiating mitosis. The fertilized egg must also stimulate translation of previously quiescent, maternally deposited mRNAs. The goal of this proposal is to increase our understanding of this critical, but incompletely understood, developmental stage of "egg activation" in the model organism Drosophila. The first specific aim focuses on the function of an important player in the fertilized egg: the "Young Arrest" (Ya) gene. YA is a maternally encoded nuclear lamina protein that is essential for male and female pronuclei to initiate their first mitotic division. Our phenotypic analysis of Ya mutants suggests either that YA mediates changes in chromatin condensation needed for passage into S phase of the first mitosis, or alternatively that it replaces a meiotic protein that is inhibitory to subsequent mitotic cycles. The experiments described in this aim will test these hypotheses for YA function, and may further identify other molecules that interact


with YA in fulfilling its roles. The results of these experiments will elucidate molecular changes necessary to transition frommeiosis to mitosis. We also expect these results to be of relevance to the mechanism of human diseases, such as Emery-Dreifuss Muscular Dystrophy, that are caused by mutations in nuclear lamina proteins. The second aim will investigate the implications of our finding that the subcellular location of YA changes during development. YA is excluded from nuclei during oogenesis, but is able to enter nuclei after egg activation. During the same transition, there are also changes in YA?s phosphorylation state. We will test whether the change in YA?s ability to enter nuclei is a direct consequence of changes in its phosphorylation state, and whether MAP kinase mediates these events. We will also identify additional components of a macromolecular complex we have identified that retains YA in the cytoplasm prior to egg activation. The third aim of the proposal is designed to achieve a broader view of the molecular events during egg activation. We will determine whether ovulation, which we have shown to trigger egg activation in Drosophila, causes a rise in calcium, parallel to findings in other systems. We will also test whether modulation of phosphorylation state, such as we see with YA, happens to many proteins during egg activation. Such modulation could mediate the rapid, concerted changes in egg physiology that occur at that time. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR DYSTROPHINOPATHIES

IDENTIFICATION

OF

CANINE

Principal Investigator & Institution: Smith, Bruce F. Associate Professor; Scott-Ritchey Research Center; Auburn University at Auburn Auburn University, AL 36849 Timing: Fiscal Year 2002; Project Start 05-AUG-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Duchenne muscular dystrophy is a common inherited disease, affecting approximately 1 in 3000 live male births. Currently, there is no effective therapy for this disease, however, new therapies are being proposed that offer hope to patients and their families. These therapies must be evaluated for their efficacy in the most stringent manner possible, and in the case of DMD, that requires an appropriate animal model. The long term GOAL of this project is to characterize the molecular defects present in 3 new canine models of dystrophin deficiency. It is hypothesized that these models accurately reflect the depth and breadth of mutations and their effects that is seen in the human population. Current murine models require that multiple genes be knocked out to show the same disease that the loss of dystrophin causes in boys. The canine model system is the only model which appropriately reflects the relentlessly progressive and ultimately fatal disease of boys. However, the complexity of the dystrophin gene and thus the variety of mutations possible, require the availability of multiple models in which to test therapies. The best source of these models continues to be spontaneously occurring canine disease. This severely handicaps the utility of these models in evaluating new therapies. This project will not only elucidate the mutation in these three new canine models, but it will also create a set of tools that will allow investigators worldwide to rapidly evaluate further spontaneous cases of canine muscular dystrophy for their usefulness, both in exploring new therapies and in gaining new insight into the mechanism behind Duchenne muscular dystrophy. Specifically, we propose to use panels of monoclonal antibodies with known specificity to dystrophin, simultaneously with PCR amplification of the coding sequence to rapidly scan for mutations. Suspicious areas will be sequenced to determine if the mutation is contained within. Once the mutations are identified, their effect on transcription, translation and the presence of dystrophin will be evaluated and

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compared to similar human mutations to determine if there is a pathophysiological correlation between species and their mutations. Successful completion of this project will result in the addition of three models of human dystrophin deficiency to the tools available to investigators seeking novel treatments. The correlation of these mutations with the clinical course of the disease will allow therapies to be evaluated under a variety of clinical circumstances. These mutations will provide new and different genetic backgrounds upon which various therapies, and in particular genetic therapies, may be examined in a large, outbred animal species. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR MECHANISMS OF MYOTONIC DYSTROPHY Principal Investigator & Institution: Timchenko, Lubov T. Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, TX 77030 Timing: Fiscal Year 2002; Project Start 01-SEP-1997; Project End 31-AUG-2007 Summary: (provided by applicant): Myotonic dystrophy (DM) is a neuro-muscular disease with a complex inheritance and an extremely complex molecular pathophysiology. We have suggested that unstable CTG repeats responsible for DM cause the disease at the RNA level via recruitment of specific RNA-binding proteins. We identified a CUG RNA-binding protein, CUGBP 1, and showed that this protein is recruited by CUG repeats into heavy RNA-protein complexes in cardiac tissue from DM patients. In order to investigate the role of CUGBP 1 in skeletal muscle differentiation, we generated primary skeletal muscle lines from DM patients and showed that a significant portion of DM cells fail to exit cell cycle during differentiation and that DM cells are able to proliferate. The failure of DM cells to differentiate is accompanying with a failure to accumulate CUGBP1 in cytoplasm. Our data show that CUGBP1 regulates translation of several mRNAs, including mRNA coding for an inhibitor of cell cycle, p21. p21 plays a key role in the differentiation of skeletal muscle. The major hypothesis of this application is that, under normal conditions, 1) CUGBP1 regulates cell cycle withdrawal in skeletal muscle via induction of p21 translation. 2) In DM skeletal muscle cells, expansion of CUG repeats within the mutant DMPK mRNA recruits CUGBP1 leading to the trapping CUGBP1 in nuclei and to inhibition of its cytoplasmic function: induction of p21. 3) The reduction of p21 in DM muscle cells results in a delay in exit from the cell cycle during muscle differentiation. Specific Aim I will define molecular mechanisms by which CUGBP1 is trapped in nuclei of DM differentiated cells. Specific Aim II examines the role of cytoplasmic CUGBP1 in p21-dependent regulation of skeletal muscle differentiation. Myoblast cell cycle progression and exit from the cell cycle will be examined in DM patients and in cell cultures with reduced levels of CUGBP 1. Specific Aim III will examine whether an increase of CUGBP 1 in nuclei of DM cells affects skeletal muscle differentiation. Myoblast cell cycle withdrawal and efficiency of myoblast fusion will be examined in cells derived from transgenic mice overexpressing CUGBP1. p21-dependent and p21-independent pathways will be examined. We will test whether other CUG repeats binding proteins are also affected in DM skeletal muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PATHOPHYSIOLOGY OF FACIOSCAPULOHUMERAL MUSCUL* Principal Investigator & Institution: Chen, Yi-Wen; Children's Research Institute Washington, D.C., DC 20010


Timing: Fiscal Year 2001; Project Start 28-SEP-2001; Project End 31-MAY-2004 Summary: (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscle diseases following Duchenne muscular dystrophy and myotonic dystrophy. The disorder is autosomal dominant with nearly complete penetrance (95%) by age 20. Severity of muscle involvement in FSHD is extremely variable, ranging from elderly individuals with mild facial weakness to wheelchair bound children. Besides variability between individual patients, FSHD patients often show enigmatic asymmetry of muscle involvement. This disease feature permits a novel experimental design, where progression of the disease can be studied within a single patient at a single time point. Previous studies showed a statistically significant correlation between severity of clinical presentation and the deletion of D4Z4 repeats on chromosome 4q35 in patients with FSHD. Current hypotheses center on a position effect of telomeric sequences on genes in or near the deletion site, however the molecular mechanisms underlying this disease are far from clear. In our study, we hypothesize that FSHD patient muscle shows a disease-specific expression profile, relative to other muscle disease (Duchenne muscular dystrophy, alpha-sarcoglycan deficiency, juvenile dermatomyositis, and dysferlin deficiency). In addition, we hypothesize that one can identify a subset of the FSHD-specific genes will be shown to correlate with progression of-muscle involvement in FSHD muscle by comparing expression changes correlated with clinically-affected vs. unaffected muscles within single dystrophy patients. In our preliminary data, we have defined an FSHD-specific set of 29 genes that are candidates for primary involvement of disease pathogenesis by using the HuGeneFL array (-6,000 full length genes). In this proposal, we plan to broaden the number of genes studied, so that a genome-wide set of genes implicated in the primary etiology can be defined. Specifically, we will extend our truly promising preliminary data to over 60,000 genes and EST sequences included on the Human genome U95A, B, C, D, E stock chips, as well as the > 2,000 human muscle ESTs on our custom-produced MuscleChip. In addition, a custom glass slide array consisting of - 200 genes and ESTs from 4q35 and lOq26 will be used to identify FSHD region specific alterations in gene expression. All FHSD-specific ESTs identified will be characterized in detail. Further studies will likely include the delineation of a complete picture of the pathophysiology of FSHD, as well as identification of functional SNPs in the refined gene list that correlate with disease severity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR STUDIES IN AUTOSOMAL DOMINANT LIMB GIRDLE MUSCULAR DYSTROPHY(LGMD) Principal Investigator & Institution: Vance, Jeffery M. Professor; Duke University Durham, NC 27706 Timing: Fiscal Year 2001 Summary: Limb Girdle Muscular Dystrophy is major form of muscular dystrophy affecting both adults and children. The autosomal recessive LGMD have made major progress in understanding these disorders through positional cloning and candidate protein analysis. We propose to take a similar approach to the autosomal dominant form of this disease. Through the previous funding period we have collected 23 autosomal dominant families (LGMD1) comprising 795 individuals. From this group we have previously linked a large family to chromosome 5 (LGMD1a). Recently, we have identified another LGMD1 locus on chromosome 7q36 (LGMD1D). In collaboration with Dr. Carol Westbrook, we have previously established a 2 megabase YAC/BAC contig across the chromosome 5 LGMD1A region and have screened 33 ESTs lying within this

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region for muscle expression. Currently, we are characterizing and evaluating positive clones for potential mutations. We propose to continue to narrow the LGMD1A minimal candidate region and perform candidate gene analysis using direct selection if needed, to identify the gene defect. Once the LGMD1A gene defect is identified, we will begin mapping the LGMD1D region on chromosome 7q36 to identify this gene defect. Physical mapping for the chromosome 7q36 region will be done in conjunction with Dr. Eric Green, who is responsible for forming contigs on chromosome 7 for the sequencing initiative of the chromosome for Washington University. Three large YAC contigs already span the current LGMD1D region, with two gaps. We will also utilize direct selection for this analysis but we anticipate sequence data to be available to assist in identifying the LGMD1D gene. Once the LGMD1A or LGMD1D gene is identified, we will work with our consultant Dr. Lou Kunkel to evaluate the function of the protein, assess the extent of mutations in small and isolated LGMD cases, and evaluate any genotype/phenotype correlations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •


MOLECULAR

STUDIES

OF

FACIOSCAPULOHUMERAL

Principal Investigator & Institution: Figlewicz, Denise A. Professor; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MTOR SIGNALING IN SKELETAL MYOGENESIS Principal Investigator & Institution: Chen, Jie; Assistant Professor; Cell and Structural Biology; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, IL 61820 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Skeletal muscle differentiation is a well-orchestrated process regulated by autocrine, paracrine, and endocrine factors via multiple signal transduction pathways. The bacterial macrolide rapamycin inhibits a wide spectrum of cellular functions, from proliferation, growth, to differentiation, and it has served as a powerful tool to probe relevant signaling pathways. While the rapamycin-sensitive pathway is under intensive investigation in the context of cell growth and proliferation, its importance in skeletal muscle development is only beginning to be recognized. The mammalian target of rapamycin - mTOR- is a multi-functional protein that serves as a central component of multiple signaling pathways that are inhibited by rapamycin. Preliminary studies from this investigator's laboratory have revealed an essential function of mTOR in skeletal muscle differentiation and the existence of novel mechanisms of mTOR signaling. The proposed studies are designed to test the hypothesis that an mTOR pathway distinct from that in cell growth and proliferation regulates skeletal muscle satellite cell differentiation by controlling the autocrine production of IGF-I and IGF-II. With a combination of biochemical, molecular, cellular and genetic approaches, and in the systems of a tissue culture model (C2C12) and mouse primary satellite cells, the specific aims of this proposal are to investigate (1) regulation of IGF autocrine production by mTOR; (2) involvement of a phospholipase D-phosphatidic acid-mTOR pathway in myogenesis; and (3) mTOR's structure-function relationship and novel signaling partners in differentiation. Knowledge gained in these


studies will not only provide invaluable insights into the signaling mechanisms of the pleiotropic mTOR pathway, but also make significant contributions to the molecular understanding of skeletal muscle development, which is tightly coupled to healthrelated issues such as muscular dystrophy, exercise-induced hypertrophy, and agingrelated atrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTIPLE PEPTIDE SYNTHESIZER - AN INTEGRATED SYSTEM Principal Investigator & Institution: Kurosky, Alexander; Professor; Human Biol Chem and Genetics; University of Texas Medical Br Galveston 301 University Blvd Galveston, TX 77555 Timing: Fiscal Year 2002; Project Start 01-MAY-2002; Project End 30-APR-2003 Summary: (provided by applicant): Support is requested for an automated solid-phase peptide synthesizer, preparative high-performance liquid chromatography equipment dedicated to peptide purification, and a vacuum concentrator for drying solvents used during synthesize and purification. This integrated system of instruments for producing synthetic peptides will replace aging ten-year-old equipment that is now unsupported by the manufacturer. The selected synthesizer, a Rainin Symphony/Multiplex with the Cascade Combinatorial Reactor, is a multiple peptide synthesizer that can synthesize up to twelve peptides simultaneously and independently, allowing us to better meet increased demands for synthetic peptides for NIH-funded researchers at the University of Texas Medical Branch (UTMB). The beneficiary users of the requested equipment include a multidisciplinary group of fourteen predominantly NIH-supported investigators (9 major and 5 minor users; 22 funded NIB grants totaling $4 million dollars annual direct costs) representing several clinical and basic science departments at UTMB, e.g. Human Biological Chemistry and Genetics, Microbiology and Immunology, Pediatrics, Pathology, Anatomy and Neuroscience, as well as Internal Medicine. Examples of diseases under investigation by these synthetic peptide users include those involving or related to muscular dystrophy, allergy, asthma, cancer, xenobiotics, environmental toxicology, mutagenesis, and gastroenterology. The Peptide Synthesis Core is one of five cores within the UTMB Protein Chemistry Laboratory; the others are the Protein/DNA Sequencing, the Proteomics, the Mass Spectrometry, and the Protein Expression Cores. Together, these core facilities provide a wide range of services for the entire University campus including multiple campus research centers. Acquisition of the requested instrumentation will significantly enhance the ability of NIH-funded investigators to conduct their ongoing hypothesis-driven research and, moreover, will extend their research opportunities in the future to higher levels of productivity and scientific impact. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MUSCLE GENE REGULATION AND CASSETTES FOR GENE THERAPY Principal Investigator & Institution: Hauschka, Stephen D. Biochemistry; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 01-MAY-1976; Project End 30-APR-2008 Summary: (provided by applicant): This project combines a basic research component aimed at understanding how muscle genes are regulated, with an applied component aimed at designing regulatory cassettes for expressing therapeutic proteins in striated muscle. Prior basic studies concentrated primarily on understanding how the mouse M-

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creatine kinase (MCK) gene enhancer and promoter control MCK expression in skeletal and cardiac muscle. These studies will continue but much of our future effort will be directed toward mapping three additional regulatory regions which confer higher transcriptional activity to the enhancer-promoter complex, and a fourth region which confers gene copy number-dependent expression. Control elements within these regions will be identified and these sequences will then be used to identify and understand the function of their associated transcription factors. Applied aspects of the project utilize the basic information above, together with published data concerning other striated muscle genes, to construct regulatory cassettes that will be useful in treating skeletal and cardiac muscle diseases, and in therapeutic situations which could benefit from using skeletal muscle as a source of secreted proteins; e.g., hormone and clotting factor deficiency diseases, and tissue healing. Goals for these studies are to optimize the transcriptional activity of cassettes designed to function in different striated muscle types, while simultaneously maintaining tight muscle-specific transcription so as to prevent therapeutic gene expression in immune system and other non-muscle cells that may be inadvertently transduced and damaged by mis-targeted gene therapy vectors. Two additional goals are to build miniature regulatory cassettes that will be compatible with packaging therapeutic cDNAs such as mini- and micro-dystrophins into AAV and other small viral vectors, and to build high activity muscle-specific cassettes expressing externally regulatable transcription factors that will selectively transcribe therapeutic cDNAs in response to non-harmful drugs, thus permitting the external manipulation of therapeutic gene product levels. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUSCLE RESPONSE TO STRESS IN CANINE MUSCULAR DYSTROPHY Principal Investigator & Institution: Childers, Martin K. Phys Med and Rehabilitation; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2001; Project Start 01-MAR-1999; Project End 28-FEB-2003 Summary: This project will provide the applicant with the research skills required to develop and assess rehabilitation treatments that enhance function for patients with muscular dystrophy. Throughout a doctoral program in physiology, a major portion of effort will be devoted to a mentored research project which will examine the relationship between mechanical stress and muscle fiber injury in a canine homolog of Duchenne muscular dystrophy. The central hypothesis of this research is that fiber damage in dystrophin-deficient muscle results, in part, from an exaggerated response to mechanical stress incurred during contraction. Furthermore, muscles involved in lengthening contractions are subject to greater stress than other muscles, and are preferentially injured. The central hypothesis will be tested in selected hindlimb muscles of dystrophic dogs by evaluating cellular and physiological features of muscle fiber response to varying levels of imposed stress. Although the mdx mouse is more readily available and a more commonly used experimental model, the dystrophic dog expresses clinical features analogous to humans with Duchenne muscular dystrophy. Aim 1 will correlate muscle membrane damage with myofiber necrosis: Aim 2 will compare regenerative features in muscles involved in lengthening contractions with muscles involved in shortening contractions: Aim 3 will determine if a lower threshold to stressinduced injury exists in dystrophic fibers compared to controls: and Aim 4 will determine if reducing mechanical stress during growth will eliminate or decrease the exaggerated fiber necrosis and remodeling seen in the adult gastrocnemius muscle. It is anticipated that findings will improve the understanding of how dystrophic muscle


responds to physical stress resulting in improved treatment for patients with Duchenne muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUSCULAR DYSTROPHY COOPERATIVE RESEARCH CENTER Principal Investigator & Institution: Moxley, Richard T. Professor; Neurology; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 31-MAY-2008 Summary: (provided by applicant): The myotonic dystrophies (DM1 and DM2), which are the most common form of adult-onset muscular dystrophy, are autosomal dominant diseases with similar clinical presentations. Remarkably, DM1 and DM2 are caused by unstable microsatellite expansions in the untranslated regions of two different genes, DMPK and ZNF9. To explain how these non-coding expansion mutations lead to dominantly inherited neuromuscular disorders, we have proposed a toxic RNA model for the myotonic dystrophies. Transcription of the mutant DM1 (CTG)n and DM2 (CCTG)n alleles leads to the production of unusual RNA transcripts with (CUG)n and (CCUG)n repeat expansions. These expansions fold into stable double-stranded (ds) RNA structures that recruit and then sequester a family of dsRNA-binding factors, the muscleblind proteins. Because this toxic RNA model suggests that DM1 and DM2 diseases are due to loss of muscleblind protein function, we have derived muscleblind 1 (Mbnll) knockout mice. This proposal is designed to test our working hypothesis that Mbnll-/- knockout mice will be a useful model to examine underlying molecular mechanisms involved in myotonic dystrophy disease pathogenesis. First, we will characterize the Mbnll-/-muscle phenotype and test the hypothesis that Mbnll is required for proper alternative splicing and function of the chloride channel CIC-1. Deficiency of this ion channel has been recently implicated as the cause of DM1- and DM2- associated myotonia. The stoichiometric relationship between toxic RNA and binding protein will be examined by breeding Mbnll knockout mice with lines of transgenic mice that express (CUG)n RNA at different levels. Second, the possibility that muscleblind proteins influence CIC-1 chloride channel levels by interacting with alternative splicing, and/or other, factors will be examined. Third, the hypothesis that the myotonia phenotype can be rescued using recombinant adeno-associated virus mediated expression of wild type adult CIC-1 will be tested. Finally, we will investigate if additional disease-associated phenotypes result from deletion of the entire Mbnll gene, from tissue-specific Mbnll expression or from combinatorial loss of all three muscleblind (Mbnll, Mbnl2/Mbnll, Mbnl3/Mblx) genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MYELOID CELL FUNCTION IN MUSCULAR DYSTROPHY Principal Investigator & Institution: Tidball, James G. Professor; Physiological Sciences; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 24-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Duchenne muscular dystrophy (DMD) is the most common, inherited, lethal disease of childhood. Although mutations in the dystrophin gene are primarily responsible for DMD and animal models of DMD, many features of dystrophinopathies indicate that secondary processes can contribute substantially to pathology. Recent findings have indicated that the immune system can contribute significantly to the pathological progression of dystrophin-deficiency in the mdx mouse

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model of the disease. The long-term goal of our studies of the pathology of dystrophindeficiency is to identify the specific immune cells and mechanisms that promote the pathology of dystrophin-deficiencies, after which we will use that information for the development of immune-based therapeutics. Although our preliminary data implicate both myeloid and lymphoid cells in promoting the dystrophic pathology, the studies proposed here will focus on cytotoxic mechanisms that are mediated by macrophages and eosinophils in dystrophic muscle. Our rationale for focusing on these specific myeloid cells is that our preliminary findings strongly implicate these cells in promoting the pathology of dystrophin-deficiency through both innate and acquired immune responses. Our general strategy will be to assess the effect on muscle pathology of depletion of specific myeloid cell populations from the dystrophic mdx mouse. In addition, the effect of those depletions on the lifespan of the dystrophic mdx/utrophindeficient mice will be assessed because these mice die from muscular dystrophy at an early age. We will also test whether introducing null mutations of the inducible nitric oxide synthase gene or major basic protein gene into mdx mice will reduce muscle pathology, because our findings implicate cytotoxic pathways in the mdx pathology that involve the products of these genes. Results of the study proposed here will permit us to determine whether therapeutic approaches that are based on reducing myeloid cell mediated pathology can be productive approaches to the treatment of these forms of muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYOGENIC GROWTH AND DIFFERENTIATION Principal Investigator & Institution: Olwin, Bradley B. Professor; Molecular, Cellular & Dev Biol; University of Colorado at Boulder Boulder, CO 80309 Timing: Fiscal Year 2001; Project Start 15-JUL-1999; Project End 30-JUN-2004 Summary: Aging, severe injury and skeletal muscle diseases all result in the loss of skeletal muscle tissue. Although skeletal muscle has a large regenerative capacity, a permanent loss of skeletal muscle tissue can occur in each of these clinical occurrences. The molecular mechanisms that regulate skeletal muscle regeneration are largely unknown. Implicated in skeletal muscle growth and regeneration are extracellular factors that include the insulin-like growth factors (IGFs), the fibroblast growth factor (FGFs), the transforming growth factor family (TGFs and GDFs), and hepatocyte growth factor (HGF). The loss of skeletal muscle function occurring in humans with muscular dystrophy and aging has been attributed to a loss of muscle regenerative capacity, but little is known concerning the mechanisms involved in this process. Myoblast transfer therapy to alleviate these symptoms is largely unsuccessful in animals and humans due to the death of greater than or equal to 95 percent of myoblasts following injection and the poor proliferative potential of the remaining cells. As an alternative, gene therapy with adenoviruses may be difficult due to the large mass of muscle tissue. It is likely that a combination of these procedures will be required to eventually cure muscle diseases and recover muscle tissue in patients exhibiting severe cachexia. In order to make myoblast transfer therapy successful, it will be necessary to manipulate the decision of a committed myoblast to proliferate, remain quiescent and undifferentiated, or to terminally differentiate and undergo cell fusion. A primary goal of the proposed research is to understand the relationships that regulate proliferation and differentiation in myogenic cells. The specific aims are to: 1. characterize the molecular mechanisms that are utilized by intracellular FGF-2 to promote myoblast proliferation; 2. analyze potential MAPK phosphatase 1 (MKP1) substrates and determine their involvement in FGF-mediated repression of skeletal muscle differentiation; 3. identify unknown MKP1


substrates that may act to mediate repression of differentiation by FGFs; 4. characterize MKP1 substrates identified in aim 3 and determine their involvement in repression of skeletal muscle differentiation. These goals will be accomplished by a combination of approaches that include the use of novel FGF-2 fusion proteins that partition into the cytoplasm via a receptor-independent mechanism, expression of mutant signal transducers, identification of unknown substrates by nanospray mass spectrometry, and determination that the identified MKP1 substrates are clinical regulators of skeletal muscle differentiation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYOSIN GENE DIVERSITY AND FUNCTION Principal Investigator & Institution: Leinwand, Leslie A. Professor and Chair; Molecular, Cellular & Dev Biol; University of Colorado at Boulder Boulder, CO 80309 Timing: Fiscal Year 2003; Project Start 01-SEP-1981; Project End 31-JAN-2007 Summary: (provided by applicant): The formation of skeletal muscle and its adaptation to the environment requires precise temporal and spatial regulation of a host of proteins, including the molecular motor protein, myosin. The precise adaptation of myosin heavy chain (MyHC) genes requires coordinate regulation, yet, little is known about its molecular biology. We propose to define the molecular aspects of fiber type specificity and the pathways that regulate these genes. In mammals, there are 6 characterized skeletal muscle MyHC genes. Although muscle fibers expressing each of them have unique contractile velocities, the enzymatic properties of the individual motors remain elusive. We will express the 6 human skeletal MyHC head domains in an inducible mammalian system and characterize their biochemical and biophysical properties. Despite the perception that the sarcomeric MyHC gene family had been defined, examination of the human genome revealed a novel striated MyHC that we propose to characterize. We have found that it is expressed in cardiac and skeletal muscle and that phylogenetically, it appears most closely related to the alpha and beta MyHC genes. We will compare the sequence features of the coding, regulatory regions and the intron/exon organization of this gene in mouse and human. We will also determine its expression in development and in the adult and test whether wellcharacterized muscle adaptations alter its pattern of expression. Until recently, there had been no diseases associated with mutations in skeletal MyHC. However, a mutation in the MyHC IIa gene has been reported which we propose to model in transgenic mice. We are also characterizing the IId gene of a childhood myopathy patient who appears to be null for its expression. An interesting feature of the MyHC gene family that may have relevance to Duchenne muscular dystrophy (DMD) is that the most abundant MyHC protein in rodents, IIb, is barely detectable in normal adults. However, we find its expression is induced in DMD. Because of the potential functional consequences of expression of this fast myosin motor, we will define the molecular basis for this species difference and its induction. Finally, we will extend our studies of an unusual cell type, the myofibroblast, which has properties of both muscle and nonmuscle cells, including expression of adult fast skeletal MyHCs, to understand the pathways that define these cells and distinguish them from skeletal muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MYOSTATIN IN MUSCLE GROWTH AND REGENERATION Principal Investigator & Institution: Wagner, Kathryn R. Assistant Professor; Neurology; Johns Hopkins University 3400 N Charles St Baltimore, MD 21218

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Timing: Fiscal Year 2001; Project Start 15-MAY-2001; Project End 31-MAR-2006 Summary: (provided by applicant): Skeletal muscle grows and atrophies in response to environmental stimuli and has an impressive ability to regenerate following a variety of insults. The processes underlying muscle growth and regeneration are incompletely understood but are apparently governed by a number of growth and differentiation factors. Myostatin, a recently described member of the TGFbeta superfamily, appears to be a negative regulator of muscle growth. Targeted deletion of the myostatin gene in nice causes widespread and massive skeletal muscle hypertrophy and hyperplasia. This study will examine the mechanism of action of myostatin and its potential role in regeneration with three specific aims. First, the precise biological function of myostatin will be defined in vivo and in vitro. Myostatin null mice will be further characterized, particularly with respect to muscle progenitor cells. The normal, cellular pattern of myostatin expression will be determined by RNA analysis of myocytes in vitro and in situ. The biological effects of purified recombinant myostatin on myocytes will be examined in primary and established cell cultures. Second, 1he main focus of the project will be to identify the receptor to myostatin. The binding affinity and distribution of receptors will be determined by binding of radioiodinated myostatin to cultured cells, tissue membranes and embryo whole mounts. The receptor will then be cloned through an approach including expression cloning. Third, the potential role of myostatin in disease and regeneration will be explored in the null mutant mouse through models of myopathy including dystrophinopathy, crush injury and toxic insult. Understanding, and potentially modulating, the factors that influence muscle growth and regeneration. have important applications to myopathies, muscular dystrophies and muscle aging (sarcopenia). The proposed research will employ a variety of molecular biology, protein biochemistry, cell culture and histopathology techniques m order to study an apparently powerful negative regulator of muscle growth. In addition to the ultimate goal of providing clinical applications for muscle disease, this multidisciplinary approach should provide excellent training for a career integrating clinical myology and molecular neuroscience. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MYOTENDINOUS JUNCTION FORMATION IN SKELETAL MUSCLE Principal Investigator & Institution: Kramer, Randall H. Professor; Stomatology; University of California San Francisco 500 Parnassus Ave San Francisco, CA 94122 Timing: Fiscal Year 2001; Project Start 01-FEB-1999; Project End 31-JAN-2004 Summary: (Adapted from investigator's Abstract): Craniofacial skeletal muscle defects occur in certain myopathies, such as muscular dystrophy; in congenital deformities, such as hemifacial microsomia and facial/palatal clefts; and as a result of surgical procedures for oral cancer or trauma. Success in the repair or replacement of muscle defects is limited by difficulty in transplantation and survival of muscle tissue. An important structure of muscle is the myotendinous junction (MTJ), which transduces force generated by muscle to its connective tissue attachment site. How this complex structure is formed in developing muscle or repaired after injury or disease is poorly understood. Attachment of the muscle fiber to the connective tissue appears to involve adhesion receptors, including the alpha7-beta1 integrin. In addition, during muscle development and repair, alpha7 integrin seems important for myoblast adhesion and motility. The long- term objective of the proposed studies is to further define the molecular mechanisms by which the laminin-binding alpha7 integrin organizes the MTJ in developing and regenerating skeletal muscle. The hypothesis is that the alternatively spliced isoforms of alpha7 not only regulate transient adhesion during myoblast motility


but also form the long-lived MTJ. The specific aims are 1) to determine the expression levels and distribution of laminin-binding integrins during skeletal muscle development, 2) to analyze the functionality of alpha7,beta1 alternatively spliced isoforms, and 3) to determine the role of the alternatively spliced extracellular domain in regulating alpha7 activation. The experimental approach is first to define the developmentally complex expression patterns of the alpha7 splice variants and their ligands. Next, alpha7 isoforms will be analyzed for their role in cell motility and assembly of MTJ-like structures. Finally, the role of the extracellular domain splice variants in regulating alpha7 activity will be addressed using molecular approaches. These studies will enhance understanding of the structure and assembly of the MTJ and suggest new approaches in tissue engineering to promote reconstruction of craniofacial skeletal muscle defects caused by disease, trauma, or surgical procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NERVE-MUSCLE SYNAPSE ORGANIZING MOLECULES Principal Investigator & Institution: Fallon, Justin R. Professor; Neuroscience; Brown University Providence, RI 02912 Timing: Fiscal Year 2001; Project Start 01-AUG-1988; Project End 28-FEB-2006 Summary: (Adapted from applicant's abstract): This proposal has two overall, interrelated goals. The first is to deepen our understanding of how synapses are formed, shaped, maintained and eliminated. The second is to elucidate how the integrity of the muscle fiber membrane is maintained, with particular regard to muscular dystrophy. Agrin secreted from the nerve terminal induces the formation of nerve-muscle synapses. The agrin signaling receptor MuSK is essential for this induction. However, agrin does not bind MuSK directly and the mechanisms of MuSK activation and localization are unresolved. In the previous funding period we discovered a novel component of Torpedo electric organ postsynaptic membranes, biglycan. Biochemical studies show that this small leucine-rich repeat proteoglycan (SLRP) binds via distinct domains to a adystroglycan, the ectodomain of MuSK and to a-and g- sarcoglycan. Both biglycan and its homolog decorin induce MuSK tyrosine phosphorylation when added to cultured myotubes. Moreover, agrin-induced AChR clustering is greatly reduced on myotubes from biglycan null (biglycan-10) mice. Finally, serum creatine kinase levels are markedly elevated in biglycan-10 mice. Together, these observations point to an important role for biglycan and/or decorin in postsynaptic differentiation, and for biglycan in maintaining the integrity of the muscle cell plasma membrane. In the present proposal we will take a combined molecular, biochemical, cell biological, and genetic approach to elucidate the role of biglycan and decorin in synaptic differentiation and in maintaining muscle cell integrity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NEUROBIOLOGY OF DISEASE -- TEACHING WORKSHOP Principal Investigator & Institution: Lipton, Stuart A. Director, Degenerative Disease; Society for Neuroscience 11 Dupont Cir Nw, Ste 500 Washington, DC 20036 Timing: Fiscal Year 2001; Project Start 01-AUG-1983; Project End 31-MAY-2006 Summary: The Society for Neuroscience (SFN) is the major professional organization for scientists who study the nervous system. An important goal of this organization is to encourage scientists in training to undertake research related to diseases of the nervous system. The objective of this grant application is to support teaching workshops that introduce young neuroscientists to current concepts about the etiology and pathogenesis

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of disorders of the nervous system. For each workshop, about 12 faculty are chosen by the Organizing Committee after eliciting proposals from the Society at large. Clinical presentations provide enrollees with an experience of the human dimension of particular diseases. Lectures cover both clinical research and relevant laboratory work. In addition to lectures, enrollees are given a choice of attending two of four small group workshops that emphasize either specific or methodological issues and encourage lively discussion. Since its inception, 20 workshops have been held, usually on the day prior to the start of the Society for Neuroscience meeting. Topics have included: Infections in the nervous system, epilepsy, Huntington's and Alzheimer's diseases, muscular dystrophy, multiple sclerosis, prion diseases, drug addiction, pain and affective disorders, stroke and excitotoxicity, neuromuscular diseases, amyotrophic lateral sclerosis, schizophrenia, migraine, mental retardation and developmental disorders, Tourette's syndrome and obsessive-compulsive disorder, and the neurobiology of brain tumors. Enrollment generally runs between 100 and 200 attendees. Most enrollees are graduate students or postdoctoral fellows. Current plans are to cover the following topics in the near future: Genes, free radicals, mitochondria and apoptosis in Parkinson's disease, AIDS dementia, peripheral neuropathy, pain, language disorders, and affective disorders. Other topics will be chosen depending on their potential interest to young neuroscientists, their impact on society and the quality of recent research related to that disease area. We are especially interested in covering diseases of the nervous system which are important clinically but which are in need of enhanced basic cellular and molecular understanding. Society members are encouraged to suggest topics in the SFN Newsletter. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NGF AND MUSCLE DEVELOPMENT Principal Investigator & Institution: Wheeler, Esther F.; University of Texas San Antonio San Antonio, TX 78249 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2006 Summary: The purpose of the study proposed herein is to determine the biological function of NGF and the NGF Receptors in muscle development. The preliminary data indicate a novel role for NGF and its two receptors (p75NTR and trk A) during myoblast proliferation and differentiation. The p75NTR, a non-catalytic receptor, is expressed by proliferating myoblasts but ceases to be expressed when myoblasts fuse to form myotubes. At some point during fusion, the other NGF receptor, trk A (a tyrosinespecific kinase receptor), begins to be expressed by the fused myotubes. The expression patterns of the NGF receptors raise the possibility that NGF plays a role in myogenesis. The working hypothesis is that NGF mediates processes that mediate the viability and organization of differentiating myoblasts and the normal homeostasis of differentiated myofibers. The results of the study will hopefully reveal effects of NGF on muscle that can be exploited for therapies for preventing or treating the muscular degeneration that accompanies neurodegenerative diseases as well as Duchene's muscular dystrophy. To determine the biological function of NGF and its receptors during myogenesis, the change of expression of the receptors will be determined at different stages of myoblast differentiation in vitro. Once cell cultures have been established that mimic receptor expression in vivo, the signaling pathways the pathways activated by the p75NTR in myoblasts will be studied. Dominant negative mutations in two of the signal transduction molecules will be used to determine pathway interactions. The spatial/temporal expression of the the trk A receptor protein will be studied in vivo in order to determine the development time the receptor becomes active. To better characterize the NGF response in myocytes, C2C12 cells will be transfected with


constructs that will make it possible to induce express the receptors at inappropriate times and the resulting cell lines will be tested for defects in development and differentiation. Finally, the muscle of null mutant mice for the two receptors will be examined in vivo and in vitro for changes in myoblast differentiation and muscle function. Taken together, the aims of the proposal will reveal new information about the role of NGF in the normal development and function of muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NON-RADIAL CELL MIGRATION IN CNS DEVELOPMENT Principal Investigator & Institution: Golden, Jeffrey A. Assistant Professor of Pathology; Children's Hospital of Philadelphia 34Th St and Civic Ctr Blvd Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 15-FEB-2003; Project End 31-DEC-2007 Summary: (provided by applicant): Epilepsy, mental retardation and structural anomalies of the brain often have a genetic etiology. Although they affect 3-5% of all children, the underlying pathogeneses for these disorders is poorly understood in most cases. Cell migration is a central component of normal central nervous system (CNS) development and disruptions in this process have been implicated in the development of multiple disorders such as Fukuyama Muscular dystrophy, Miller-Dieker Syndrome, Walker-Warburg Syndrome, and the Muscle-Eye-Brain syndrome to name just a few. Two primary patterns of cell migration are recognized during CNS development, radial and non-radial. While the cellular and molecular bases of radial cell migration, long considered the predominant mode of cell migration, have begun to be defined, the mechanisms of guidance for non-radial cell migration remain largely unexplored. Using lineage analysis, we have defined the developmental time and location where non-radial cell migration begins in the chick forebrain. Based on these data we have developed a model to explain the cellular and molecular mechanisms of non-radial cell migration. Our model is based on the hypotheses that cell surface molecules, secreted molecules, and extracellular matrix molecules guide non-radially migrating cells. This proposal will begin to address our hypothesis by 1) directly testing several components of our model, and 2) generate a mammalian model to further study one of the molecules we have identified as a component of non-radial cell migration in the chick. These data will certainly enhance our understanding of normal CNS development. Furthermore, we anticipate the data from these studies will provide insight into the pathogenesis of a variety of inherited and non-inherited conditions that afflict children such as epilepsy, mental retardation and structural malformations of the brain. This may ultimately lead to improvements in the diagnosis, management, and prevention of neurological diseases where abnormal cell migration has a pathogenetic role. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NOVEL APPLICATION OF STEM CELLS/ RETROVIRAL VECTORS Principal Investigator & Institution: Mulligan, Richard; Dana-Farber Cancer Institute 44 Binney St Boston, MA 02115 Timing: Fiscal Year 2001 Summary: Recent studies from our laboratory and others suggest that murine hematopoietic stem cells and perhaps other cell populations derived from nonhematopoietic organs, may possess the capacity to differentiate into a range of mature cell types distinct from those originally thought to be derived from the cells. This apparent 'plasticity' of stem cell populations offers new opportunities to expand the use of bone marrow transplantation, in conjunction with gene transfer, to treat congenital

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diseases which affect cells other than those of the blood. Such a strategy may be particularly important for the treatment of diseases in which the systemic delivery of cells or genes throughout the body is essential, such as muscular dystrophy. In this research program, we propose to (i) determine, in a comprehensive way, the spectrum of cell types than can be derived from different populations of stem cells isolated from the adult, (ii) to develop procedures for the isolation, manipulation, and transplantation of cells which lead to the optimized production and systemic engraftment of specific cell types, and (iii) to apply those procedures, along with the methods we have previously developed for the transduction of hematopoietic stem cells, to the evaluation of gene therapies for the treatment of specific congenital disease, using well characterized animal models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OXANDRIN (OXANDROLONE) IN THE TREATMENT OF CHRONIC MUSCLE DISEASES Principal Investigator & Institution: Rutkove, Seward B.; Beth Israel Deaconess Medical Center St 1005 Boston, MA 02215 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF A NOVEL LIMB-GIRDLE MUSCULAR DYSTROPHY Principal Investigator & Institution: Hirano, Michio; Assistant Professor; Neurology; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 31-JUL-2004 Summary: Since the initial identification of mutations in the dystrophin gene as the cause of Duchenne and Becker muscular dystrophies, molecular genetics has provided a plethora of new information and insights into the pathogeneses of muscle diseases. In particular, our understanding of the limb-girdle muscular dystrophies (LMGD) have been greatly enhanced. Fourteen forms of LGMD have been identified; of these, specific gene have been characterized in ten. This goal of this proposal is to identify the molecular genetic basis of a fifteenth form of LGMD which has been transmitted in an autosomal dominant fashion in a large Spanish pedigree (Spanish autosomal dominant LGMD [SAD- LGMD]). The disease locus has been mapped to a seven centimorgan region of chromosome 7q31.3-32 with a maximum two-point LOD score of 7.59 with marker D7S2519. We will attempt to reduce the size of the disease locus by fine mapping studies. Candidate genes will be screened until the disease mutation is identified. The pathogenesis of the disease will be studied by studying the expression of the gene messenger RNA and the gene product in the patients' skeletal muscle and in tissue culture using cells from patients. A mouse model of the disease will be produced to further investigate the pathogenesis. Muscle biopsies from more than 50 patients with LGMD of unknown etiology will be screened for defects of the SAD-LGMD gene product. The identification of the cause of SAD-LGMD will expand our understanding of the disease and will likely enhance our general understanding of skeletal muscle functions and structure. For the patients, achieving the proposed goals will allow more accurate prenatal diagnosis, genetic counseling, and perhaps contribute to more rational therapies in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


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Project Title: PATHOGENESIS OF EMERY-DREIFUSS MUSCULAR DYSTROPHY Principal Investigator & Institution: Worman, Howard J. Associate Professor; Medicine; Columbia University Health Sciences New York, NY 10032 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): Emery-Dreifuss muscular dystrophy (EDMD) is characterized by region muscle contractures, slow progressive muscle wasting and cardiomyopathy with atrioventricular conduction block. Indistinguishable forms of EDMD are inherited in autosomal dominant and X-linked manners. Mutations in emerin, an integral protein of the nuclear envelope inner membrane, cause X-linked EDMD. Autosomal dominant EDMD is caused by mutations in the LMNA gene, which encodes the nuclear envelope intermediate filament proteins lamins A and C. It is not known how mutations in nuclear envelope proteins cause muscular dystrophy. We hypothesize that mutations in these chromatin-associated proteins cause changes in the expression of genes responsible for muscle cell differentiation or survival. Our goal is to test this hypothesis using a combination of studies in transfected cells, patients' cells and tissues and animals models. In the first specific aim, we will use fluorescence microscopy and photobleaching methods to investigate how lamin A and C mutants from patients with autosomal dominant EDMD influence the mobility of emerin in the inner nuclear membrane. We will determine if mutant lamins A and C cause emerin to "escape" from the inner nuclear membrane into the continuous endoplasmic reticulum. As patients with X-linked EDMD do not have emerin in the inner nuclear membrane, this finding would demonstrate a connection between the X-linked and autosomal dominant forms of the disease. In the second aim, we will use microarrays to compare gene expression in cells from patients with autosomal dominant EDMD to X-linked EDMD and Dunnigan-type partial lipodystrophy, a disease caused by mutations in different regions of lamins A and C. This will establish if emerin and lamin mutations responsible for EDMD alter expression of the same genes. We will also use microarrays to determine gene expression profiles in muscles from lamin A/C "knockout" mice that develop muscular dystrophy and compare the results to what is known about pathologic alterations in gene expression in Duchenne muscular dystrophy. The results will be confirmed in tissues from human subjects with EDMD. In Aim 3, we will generate transgenic mice expressing human lamin A mutants and determine if they develop pathological abnormalities of EDMD and similar gene expression changes. This work will help establish how abnormalities in the nuclear envelope cause muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PATHOGENESIS OF LAMININ-ALPHA2 DEFICIENCY Principal Investigator & Institution: Miller, Jeffrey B.; Boston Biomedical Research Institute 64 Grove St Watertown, MA 02472 Timing: Fiscal Year 2002; Project Start 19-SEP-2002; Project End 31-AUG-2006 Summary: (provided by applicant): Pathogenesis of laminin-ot2-deficiency. Mutations in the human LAMA2 gene cause congenital muscular dystrophy, group 1 (CMD 1), a devastating, recessive disease of childhood. LAMA2 encodes laminin-c Beta 2, an extracellular protein that is abundant in skeletal muscle. The proposed experiments will test hypotheses about how loss of laminin-c_2 leads to the severe neuromuscular dysfunction in CMD1. For Aims 1 & 2, we will examine the role of apoptosis in CMD1 pathogenesis. In culture, laminin-cz2-deficient myotubes are unstable and die by a process that is inhibited by the antiapoptosis protein Bcl-2. It is not known, however,

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whether apoptosis is important in the loss of CMD1 neuromuscular function in vivo. The proposed experiments willdetermine how disease in laminin-c_2-deficient mice is affected by targeted alterations of Bcl-2 family members. For Aim 3, we will determine if muscle stem cell function is altered in CMD 1. Postnatal muscle contains multipotent stem cells, but no studies have examined these recently identified stem cells in diseased muscle. We will test the possibility that laminin- Beta 2-deficiency activates proliferation and alters the differentiation capability of these rare cells. For Aim 4, we will determine if inappropriate re-entry into the cell cycle occurs in affected tissue. Inappropriate cell cycling can lead to death of normally post-mitotic cells including neurons and myofibers. We hypothesize that laminin-cz2-deficiency alters signal transmission resulting in dysregulation of the cell cycle. To test this hypothesis, we will determine if cell cycle regulators are inappropriately induced in laminin-c beta 2-deficient cells. The results will increase our understanding of CMD 1 pathogenesis and could suggest new routes to therapy, perhaps based on apoptosis inhibition, stem cell repair, or cell cycle inhibition. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PATHOPHYSIOLOGY OF OCULOPHARYNGEAL MUSCULAR DYSTROPHY Principal Investigator & Institution: Thornton, Charles A.; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PEDIATRIC BONE GROWTH, DENSITY, AND METABOLISM Principal Investigator & Institution: Henderson, Richard C. Professor; Orthopaedics; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 30-JUN-2004 Summary: Diminished growth, deformity, osteopenia noted on plain radiographs, and frequent osteoporosis-related fractures are evidence of problems with bone growth and metabolism in many children with an assortment of medical and physical conditions. Although these very late consequences are clinically apparent, the problems are usually initially silent during the important years of skeletal growth and development. The Midcareer Award is requested to support the Research Plan of Dr. Richard Henderson, MD, PhD. He is Professor of Orthopaedics and Pediatrics at the University of North Carolina, and in this capacity is a clinically active pediatric orthopaedic surgeon. Dr. Henderson also has a long-standing commitment to clinical research, with proven productivity. His primary research focus is on the issues of osteoporosis, fractures, and bone growth and metabolism in various pediatric conditions such as cerebral palsy, cystic fibrosis, milk allergy, chemotherapuetically treated malignancies, and muscular dystrophy. In the first phase of his Research Plan techniques for assessing bone growth, density, and metabolism are adapted to the unique features of handicapped children. The first phase also includes several single-site, observational, cross-sectional and longitudinal studies with the specific aim of assessing the potential impact of these assorted conditions on mineralization of the immature skeleton. This phase of the Research Plan has just been completed. The second phase includes projects designed to better characterize bone growth and metabolism in children with cerebral palsy, and to


assess in greater detail the prevalence, causes, and outcomes of osteoporosis in this population. The utility of this information depends in great part on the availability of prevention and/or treatment alternatives. The bisphosphonates are a class of medications used for the treatment of osteoporosis in elderly adults, and limited anecdotal data suggest that these drugs are also effective in children. The second phase of the Research Plan includes the first controlled clinical trial assessing the safety and efficacy of these drugs in a pediatric population. Extensive collaboration with other research centers brings greater statistical power and expertise in nutrition to studies in the second phase. The second phase consists of 5 closely inter-related projects over a 2-3 year time span, and data collection recently began in April 1998. The third phase planned for the years 2001-2004 will involve larger-scale clinical trials assessing bisphosphonates for the treatment of osteoporosis in multiple pediatric conditions. The practicalities of drug treatment in clinical practice and the dose-response relationship are important issues that will be addressed in this phase. The Midcareer Award is requested to support the second and third phases of the Research Plan. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHYSIOLOGY OF RESPIRATORY MUSCLE MIRCO MECHANICS Principal Investigator & Institution: Boriek, Aladin; Assistant Professor of Medicine and Phys; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, TX 77030 Timing: Fiscal Year 2001; Project Start 01-MAR-2001; Project End 28-FEB-2005 Summary: We propose to investigate the mechanisms of force transmission in skeletal muscles. In particular, we will investigate the contribution of desmin and dystrophin, intracellular components of the membrane cytoskeleton, the membrane receptor alpha7-integrin, and the extracellular molecular merosin to force transmission in diaphragm muscle. Desmin deficiency leads to desminopathy, a rare disease. Deficiencies of dystrophin, merosin, or alpha-7-integrin lead to various form of muscular dystrophy, which are more common diseases. Lack of any of these proteins causes skeletal muscle degeneration, chronic inspiratory muscle weakness, and ultimately respiratory insufficiency that leads to respiratory failure and eventually death. The diaphragm, unlike most other skeletal muscles, is loaded biaxially in vivo. That is the diaphragm experiences loads along muscle fibers and transverse to fibers during contractile activity. This application is an initial first step towards understanding the mechanical behavior of diaphragm muscle at the cellular level. Our central hypothesis is that force transmission in the diaphragm is modulated by transverse fiber loading and mediated by the linkage of specific intra- and extracellular members of the transmembrane protein network. This hypothesis will be tested by studying spontaneous and engineered mutant mouse strains; using strains missing key elements of the transmembrane protein network, we will test the response of the biaxial mechanical properties of the diaphragm and hindlimb muscles to the absence of these proteins. The long term goals of this research program are to understand muscle force transmission in skeletal muscles at the protein level and build a detailed model of mechanical coupling in normal skeletal muscles that explains the mechanism(s) by which force is transmitted from cytoskeleton to extracellular matrix. The specific aims of this project are to determine passive mechanical properties of the mouse diaphragm and their influence on contractile function and to evaluate the role of intracellular, transmembrane, and extracellular elements on the biaxial transmission of force in the diaphragm. Using a electron microscopy and biaxial loading technique applied to whole diaphragm and limb skeletal muscles in vitro, we will test the following hypotheses at both tissue and sarcomere levels: (1) transverse stress mediates force transmission in the normal diaphragm at both

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tissue and at sarcomere levels, and both passive and contractile properties of the diaphragm are altered by the presence of transverse stress; (2) intracellular members of the transmembrane protein network, desmin and dystrophin, are essential in integrating transverse and longitudinal mechanical properties of the diaphragm, and the strength of the mechanical linkage between myofibrils and the plasma membrane is determined primarily by these proteins; and (3) the mechanical coupling between myofibrils and extracellular matrix is crucial to force transmission along and transverse to the fibers in normal skeletal muscles, and force transmission is compromised by loss of either alpha7-integrin or merosin. These aims address the mechanism(s) by which force transmission is mediated by specific cytoskeletal and extracellular proteins in skeletal muscles. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POLYCYSTIN-1 INTERACTION WITH TSC-2 IN POLYCYSTIC KIDNEY DISEASE Principal Investigator & Institution: Guan, Kun-Liang; Associate Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-AUG-2008 Summary: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic disorders in humans. In the United States, ADPKD is more common than cystic fibrosis, Huntington's disease, and muscular dystrophy. ADPKD is characterized by the formation of cysts in kidney and caused by mutation in either PKD1 (85%) or PKD2 (15%) gene. Tuberous sclerosis (TSC) is an autosomal dominant inheritable genetic disorder due to mutation in either TSC1 or TSC2 gene. TSC is characterized by formation of hamartomas in various tissues. Cyst formation in kidney is also observed in TSC. The PKD1 and TSC2 genes are located adjacent to each other on human chromosome 16p and deletion of both genes results in a contiguous gene syndrome responsible for the severe infantile polycystic kidney disease. TSC2 has been implicated to play a role in the proper functions of polycystin-1, the product of PKD1 gene. The long-term goals of this project are to understand the functional relationship between TSC2 and PKD1 and to elucidate the molecular mechanism of TSC2 in regulation of PKD1 function and ADPKD. The specific aims of this proposal are to elucidate the mechanism of TSC2 regulation by osmotic stress and to investigate the function of TSC2 in regulation of the plasma membrane localization of polycystin-1. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: POSTISOPRENYLATION PROCESSING AND THE NUCLEAR LAMINA Principal Investigator & Institution: Young, Stephen G. Professor; J. David Gladstone Institutes 365 Vermont St San Francisco, CA 94103 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The proteins of the nuclear lamina have generated enormous interest because of recent studies showing that mutations in the gene for lamin A/C (LMNA) develop a host of different diseases, including cardiomyopathy, muscular dystrophy, and partial lipodystrophy. The objectives of this proposal are to define the enzymes that are important in the posttranslational processing of the nuclear lamins and to understand the consequences of defective posttranslational processing at both the cellular and tissue levels. Prelamin A (664 amino acids) terminates with a "CAAX" sequence motif and undergoes a complicated series of posttranslational


modifications. First, the cysteine (C) of the CAAX motif is farnesylated by protein farnesyltransferase. Second, the last three amino acids of the protein (i.e., the -AAX) are released by a prenylprotein-specific endoprotease (likely Rce1 or Zmpste24 or both). Third, the newly exposed farnesylcysteine is methylated by isoprenylcysteine carboxyl methyltransferase (Icmt), a membrane protein of the endoplasmic reticulum. Fourth, once the cell has gone to all of this effort, the carboxyl-terminal 15 residues of the protein (including the farnesylcysteine methyl ester) are clipped off and degraded, leaving mature lamin A (646 amino acids). Zmpste24 might carry out that final endoproteolyticprocessing step. Lamin B1 and B2 have a CAAX sequence motif and undergo the first three processing steps, but do not undergo a second endoproteolysis step; thus, their sequences terminate with a methylated farnesylcysteine. During the past few years, the laboratory of Dr. Stephen Young has generated knockout alleles [as well as some conditional ("floxed") alleles] for many of the genes involved in CAAX protein processing (e.g., Fntb, Rce1, Zmpste24, and Icmt) for the purpose of analyzing the importance of the posttranslational processing steps. In mice lacking Zmpste24, the processing of prelamin A to lamin A was blocked. Of note, the Zmpste24-deficient mice exhibited reduced muscle strength (suggestive of a laminopathy), and also developed spontaneous bone fractures, a peculiar finding not generally observed in humans with lamin mutations. The first aim of this grant application is to define, biochemically, the precise role(s) of Zmpste24 in prelamin A processing. The second aim is to further define the cellular and tissue pathology of Zmpste24 mice and then to determine whether all of the pathologic findings are due to defective prelamin A processing. The third aim is to understand the posttranslational processing of lamin B1 and to define the consequences of lamin B1 deficiency in mammals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POSTTRANSLATIONAL PROCESSING BY ZMPSTE24 AND LAMINOPATHY Principal Investigator & Institution: Ng, Jennifer K.; J. David Gladstone Institutes 365 Vermont St San Francisco, CA 94103 Timing: Fiscal Year 2003; Project Start 26-MAR-2004 Summary: (provided by applicant): The proteins of the nuclear lamina have generated enormous interest because missense mutations in LMNA (the gene for prelamin A, which encodes both lamin A and lamin C) cause a host of diseases, including EmeryDreifuss muscular dystrophy, limb-girdle muscular dystrophy, Charcot-Marie-Tooth type II peripheral neuropathy, and Hutchinson-Gilford progeria syndrome. Prelamin A, the precursor to mature lamin A, undergoes a series of posttranslational modifications, including the covalent attachment of a lipid to the protein, proteolytic clipping of the protein, and methylation of the protein. These post-translational modifications are important both to the targeting of the lamins to the nuclear envelope and to their function. The laboratory of my mentor, Dr. Stephen G. Young, recently identified an endoprotease, Zmpste24, that is required for the maturation of prelamin A to lamin A. Interestingly, Zmpste24-deficient mice develop a muscle weakness phenotype I strikingly similar to that observed in mice lacking lamin A/C. A key objective of my application is to define the pathological and molecular underpinnings of the possible muscular dystrophy, peripheral neuropathy and progeria phenotype in Zmpste24deficient mice, as well as compare them to mice harboring mutant Lmna alleles. Finally, I will investigate the consequences of defective posttranslational processing of lamin A on a cellular level in order to elucidate the biochemical role of Zmpste24 in prelamin A processing.

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Project Title: PROBING THE GATING MECHANISM OF SK CHANNELS Principal Investigator & Institution: Bruening-Wright, Andrew H. None; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2002; Project Start 14-SEP-2002 Summary: (provided by applicant): Small conductance calcium-activated potassium channels (SK channels) are fundamental regulators of neural excitation, important for setting interspike intervals, influencing burst firing patterns, and for their hyperpolarizing role in tonic membrane oscillations. They have been implicated in the disease myotonic muscular dystrophy, linked to memory and learning processes, and their normal expression is important for respiration and parturition. Cloning and heterologous expression of SK channels has allowed characterization of their fundamental properties, and biophysical, molecular biological, biochemical, and crystallographic techniques have proven that calcium gates SK channels entirely by an associated subunit, calmodulin (CaM). Thus the calcium-sensor CaM binds to a domain of approximately 100 residues in the C-terminus of SK, the CaMBD, and transduces its own calcium-induced structural changes to the SK channel, thereby opening and closing the channel. The CaM-CaMBD crystal structure has recently been solved in the presence of calcium, and provides an excellent model for testing how SK channels gate. Since specific interaction sites between CaM and the CaMBD are now known, stabilization of these interactions can distinguish regions of the complex that must move in order for the channels to gate. By determining how SK channels move during gating, insight will be gained into the molecular movements that underlie the function of this important class of ion channel. A fundamental understanding of SK gating has implications for all calcium-gated ion channels, with potential biomedical applications such as the design of drugs which modulate SK gating. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROGRAM PROJECT GRANT Principal Investigator & Institution: Uitto, Jouni J. Dermatology/Cutaneous Biology; Thomas Jefferson University Office of Research Administration Philadelphia, PA 191075587 Timing: Fiscal Year 2002; Project Start 15-AUG-1987; Project End 31-MAR-2007 Summary: This renewal application proposes extensive and innovative studies focusing on the molecular genetics of the cutaneous basement membrane zone (BMZ) towards delineating the molecular basis of various forms of epidermolysis bullosa (EB) and other selected genodermatoses affecting the epidermis. The proposed studies are designed to test the hypothesis that genetic lesions in structural genes expressed in the epidermis underlie variants of these diseases, and that the precise phenotype and mode of inheritance depend on the types and combinations of specific mutations in distinct genes. This application is based on solid progress in this project, including (a) expansion of the molecular basis of the recessive dystrophic forms of EB allowing refinement of genotype/phenotype correlations; (b) identification of novel and de novo COL7A1 mutations in dominant DEB, with an impact on genetic counseling of the families at risk of recurrence; (c) identification of a large number of novel and recurrent mutations both Herlitz and non-Herlitz junctional EB; (d) identification of uniparental disomy of chromosome 1 as a novel mechanism for H-JEB; (e) demonstration in mutations in the genes ITGA6 and ITGB4 encoding alpha-6-beta-4 integrins subunit polypeptides in EB


with pyloric atresia,; (f) cloning of the human plectin gene and demonstration of mutations in EB with late-onset muscular dystrophy; (g) cloning of mouse type VII collagen and desmoglein 3 genes with development of "knock-out" mice with blistering phenotype; (h) identification and characterization of several novel genes expressed into the epidermis, including periplakin, ladinin, and desmo-15; (i) refinement of RNADNA chimeric oligonucleotide technology for repair of the mutated genes in heritable skin diseases. This proposal details continuation of concentrated, multi-disciplinary studies in five highly interdependent projects: Project 1, "Molecular Genetics of EB and Other Heritable Disorders of the Cutaneous BMZ and Epidermis," will provide precise information on the specific mutations in the gene/protein system that are at fault in various forms of EB and other epidermal heritable disorders. Project 2, "Identification and Characterization of Candidate Genes/Protein Systems Expressed in the Skin," will provide new gene probes and information about novel genes as potential candidate genes for epidermal genodermatoses. Project 3, "Consequences of the Mutations at the Protein Structure/Function Level" will examine the structural and functional alterations that result from distinct mutations in the candidate genes, utilizing computer modeling and monitoring functional interactions in biosensor analysis system. Project 4, "Development and Testing of Animal Models for EB," will generate novel animal models for EB. Project 5, "Development of Non-Viral Gene Therapy for Cutaneous Diseases," will concentrate on testing gene therapy approaches utilizing RNA/DNA chimeric oligonucleotide strategies. These multidisciplinary studies are expected to provide precise information of critical importance for translational applications towards development of refined classification, genotype/phenotype correlations, basis for genetic counseling, and prenatal testing, as well as providing the basis for novel gene therapy approaches for this devastating group of skin diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PROPERTIES CHROMATIUM VINOSUM

OF

MOLECULAR

CHAPERONES

FROM

Principal Investigator & Institution: Torres-Ruiz, Jose A. Associate Professor; Ponce School of Medicine G.P.O. Box 7004 Ponce, PR 00731 Timing: Fiscal Year 2001; Project Start 30-SEP-1986; Project End 31-MAY-2005 Description (provided by applicant): One of the most challenging problems in Cell Biology is to understand the mechanisms by which Molecular Chaperones assist protein folding in nature. These mediators have been implicated in a wide range of fundamental biological events including; preventing formation of proteinaceous aggregates, promoting assembly and/or disassembly of oligomeric enzymes, and aiding in the protein translocation process. The emerging evidence suggests that Chaperones are ubiquitous and there is intensive interest in unraveling the precise molecular events by which this class of proteins functions at the cellular level. Moreover, recent studies conclusively demonstrate that the etiology of a variety of pathological conditions could be explained based in alterations in the expression and function of Molecular Chaperones. For instance, alterations in the expression and activation of these mediators have been convincingly demonstrated in the development of autoimmune diseases, viral and bacterial infections, cancer, and muscular dystrophy. During the last few years, we have been able to identify and biochemically characterize three Chaperones, Cpn60, Cpn10 and Hsp70 from the bacterium C. vinosum, and more. Recently, we been have successful in identifying other Chaperone systems, from the same organism, which appear to be homologs of the DnaJ, GrpE and ClpB families. Some of these mediators suffer phosphorylation and, in the present application we intend to obtain information

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in regards to the biological significance of this finding. The hypothesis to be tested in this proposal is that the ability of Chromatium vinosum Cpn60 in modulating protein folding events is controlled by protein phosphorylation and by its direct physical interaction with other Molecular Chaperones. This hypothesis will be tested by pursuing the following specific aims: (1) to evaluate the influence of various Molecular Chaperone Systems; DnaK, GrpE, DnaJ, Cpn10 and CIpB, in modulating the autophosphorylation of Cpn60 from C. vinosum; (2) to study the ability of Cpn60, in combination with other Chaperone systems, to favor disaggregation and refolding of denatured proteins; (3) to study the intracellular location of various Chaperone systems from C. vinosum, namely DnaK, DnaJ, GrpE, ClpB, and Cpn60/Cpn10, under heat shock and other stressful conditions; (4) to study the conditions that favor the Cpn60 binding to the cytoplasmic membranes of C. vinosum; (5) to study the properties of phosphorylated Cpn60 from C. vinosum under heat shock conditions and; (6) to study the impact of the Cpn60 catalyzed phosphorylation on the functional properties of RuBisCO. Results from these experiments promise to advance our understanding on the mechanisms by which Chaperones modulate protein folding. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF SKELETAL MUSCLE REGENERATION Principal Investigator & Institution: Li, Yi-Ping; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, TX 77030 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Tumor necrosis factor-alpha (TNF-alpha) is traditionally recognized as a circulating mediator that stimulates muscle catabolism in inflammatory diseases. However, recent discoveries indicate that TNF-alpha plays a more complex and more fundamental role in skeletal muscle. It is now clear that skeletal myocytes constitutively express TNF-alpha. Biological processes that demand myofiber regeneration - degenerative muscle diseases (inflammatory myopathies and Duchenne muscular dystrophy), injury and exercise -- accelerate TNF-alpha expression by myocytes. Further, it is increasingly evident that TNF-alpha is critical for muscle regeneration because it accelerates myogenic gene expression. Based on growing evidence from our and other laboratories, we propose that TNF-alpha functions as an autocrine/paracrine modulator of muscle regeneration by promoting the expression of adult-type muscle proteins during early differentiation via activating MADS-box myogenic factors, MEF2 and SRF, and a muscle hypertrophy mediator GATA-2. Three specific aims will be pursued to test this model. Aim 1. To evaluate upregulation of TNF-alpha as an autocrine modulator of primary myoblast differentiation. TNF-alpha expression during differentiation induced by distinct stimuli (serum restriction, cell confluence and cyclic stretch), and effects of TNF-alpha on adult-type muscle protein expression during differentiation will be determined in rat and mouse primary myoblasts. Aim 2. To determine whether TNF-alpha promotes muscle regeneration in vivo. Effects of TNF-alpha deficiency on muscle regeneration evoked by cardiotoxininduced muscle injury will be evaluated in mice with genetic or immunological blockade of TNF-alpha receptors. Muscle histology, contractile force generation, and myogenic gene expression will be determined to evaluate regeneration. Aim 3. To determine signaling events by which TNF-alpha stimulates myogenic differentiation. TNF-alpha stimulation of MEF2, SRF, and GATA-2, and the underlying signaling mechanisms will be evaluated. Our long-term objectives are to understand the role of cytokines as an emerging group of muscle regeneration modulators, and to improve the treatment of degenerative muscle diseases.



Project Title: REGULATION OF UTROPHIN PROMOTER IN MUSCLE Principal Investigator & Institution: Khurana, Tejvir S. Assistant Professor; Physiology; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Timing: Fiscal Year 2003; Project Start 15-MAY-2003; Project End 30-APR-2008 Summary: (provided by applicant): Utrophin (dystrophin related protein) shares extensive sequence homology and organizational motifs with dystrophin, and is considered to be the autosomal homolog of dystrophin. Indeed, transgenic over expression of utrophin can functionally substitute for the missing dystrophin molecule and reverse the dystrophic patho-physiology in the muscles of mdx (dystrophic) mice. The utrophin gene, while ubiquitously expressed, has a highly regulated sub-cellular distribution during development, regeneration as well as in mature skeletal muscle. In mature myofibers (elongated multi-nucleated cells), utrophin is enriched at the synapse or neuromuscular junction (NMJ). The spatial distribution of utrophin in myofibers parallels the distribution of nicotinic acetylcholine receptors (nACHR) to a remarkable degree, in particular, the manner in which they are influenced by the release of growth and differentiation factors (e.g. heregulin) from motor nerves. Selective enrichment of nACHR and utrophin at the NMJ occurs, in part, due to their messages being preferentially transcribed at sub-synaptic nuclei rather than nuclei scattered along the length of the myofiber. We and others, recently demonstrated that the neurite-associated growth factor heregulin utilizes the ERK (MAP kinase) signaling pathway to promote the binding of the GABPa/b transcription factor complex to the N-Box motif of the utrophin promoter, thus activating the promoter and increasing utrophin gene expression in cultured muscle cells. Current hypotheses on the regulation of utrophin expression in muscle center on N-box dependent compartmentalized transcription of utrophin at sub-synaptic nuclei. We hypothesize that additional trans-acting factors exist and regulate the utrophin promoter. We also hypothesize that co-operability among these trans-acting factors and signaling pathways plays a role in utrophin promoter regulation. In our preliminary studies, we have identified additional transacting factors, their signaling pathways and describe their co-operability in utrophin promoter regulation; we have also studied heregulin mediated utrophin promoter activation in mouse muscle, in vivo. In this proposal we plan to extend these studies to better understand the molecular mechanisms of utrophin promoter regulation in skeletal muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RES FACIL: MUSCULAR DYSTROPHY Principal Investigator & Institution: Roth, Paul B. Clinical Research Center; University of New Mexico Albuquerque Controller's Office Albuquerque, NM 87131 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 14-SEP-2003 Summary: (provided by applicant): The UNM is requesting funds to construct a new building to house several key neuroimaging modalities magnetic resonance imaging (MRI), Electron Paramagnetic Resonance (EPR), magnetoencephalography (MEG) and electroencephalography (EEG), plus a Cellular and Molecular Biology core, so that the investigators can carry out a truly multimodal neuroimaging research on the same animals. This building is planned as the animal component of a comprehensive neuroimaging facility that will also include an expanded facility (whole-head MEG and EEG, high-field MRIs) for human research. The funding in 2001 from the Institutional

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Development Award (IDeA) program [1P20RR15636, Principal Investigator (PI), Dr. Yoshio Okada] has generated an enormous level of enthusiasm at the UNM. The IDeA funding has enabled UNM to purchase several key pieces of imaging equipment (4.7T MRI, EPR and 2-photon microscope) that can be combined with the existing set of equipment for MEG, EEG and the supporting Cellular and Molecular core to carry out a multimodal neuroimaging research. These imaging modalities will be all housed in the proposed building. The physical proximity of the core facilities will enable UNM researchers to produce unique results that will provide the edge necessary to be competitive at the national level for National Institutes of Health (NIH) funding. This will be crucial for building a long-term research program that will be competitive for many years to come, beyond the five-year funding period (2/2001-1/2006) of the UNM COBRE. The UNM is providing $1,065,373 to support this application. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESCUE ANALYSIS OF UTROPHIN & NMJ SUPPORT BY SYNTROPHIN Principal Investigator & Institution: Sealock, Robert W. Associate Professor; Cellular/Molecular Physiology; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, NC 27599 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The syntrophins are a family of peripheral membrane adapter proteins that function in association with dystrophin, utrophin, and the dystrobrevins, all of which are proteins of the surface membrane of skeletal muscle and implicated in the important human disease, Duchenne muscular dystrophy (DMD). Alpha-syntrophin is the major syntrophin in muscle. In the alpha-syntrophin knockout mouse, the postsynaptic membrane at the neuromuscular junction shows major biochemical and morphological defects including low amounts of acetylcholine receptors and acetylcholinesterase, a complete absence of utrophin, immature appearing contacts, junctional folds that are disorganized and few in number, and altered distribution of AChR. Thus, there is a utrophin and NMJ support function of alphasyntrophin. The first two aims of the project are to intended to extend current understanding that the other syntrophins of muscle (beta1, beta2, and probably gamma2) are not redundant with alpha-syntrophin. They are: 1) Test the hypothesis that transgenically expressed beta 1-syntrophin will restore utrophin to adult alphasyntrophin 4- junctions but will not rescue other, or all other, aspects of the phenotype. 2) Test the hypothesis that transgenically expressed beta 2-syntrophin will restore no aspects of the alpha-syntrophin -/- phenotype. The results will provide a solid framework for molecular analysis of the mechanisms of the support function. Aim 3) Identify the critical functional domains of the alpha-syntrophin molecule by transgenic expression in alpha-syntrophin -/- mice of a) chimeric proteins containing domains of beta substituted into alpha-syntrophin (or the converse, alpha into beta) and/or b) alpha-syntrophin specifically mutagenized at selected sites. The results will identify domains and implicate syntrophin-dependent pathways. Aim 4) Determine whether low levels of utrophin mRNA, inability of the membrane to accept utrophin incorporation, or both contribute to the lack of utrophin at alpha-syntrophin -/- NMJs. If applicable, use these tools to analyze the transgenic mice. 5) Seek to identify determinants in the AChR accumulation pathway-- AChR mRNA levels, total AChR expression, cell surface AChR expression, AChR clustering response to agrin, stability of agrin-induced clusters--that may contribute to the low AChR content of alpha-


syntrophin 4- NMJs. If applicable, use the understanding so generated to analyze the transgenic mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RNA DOMINANCE IN HUMAN DISEASE Principal Investigator & Institution: Swanson, Maurice S. Associate Professor; Molecular Genetics & Microbiol; University of Florida Gainesville, FL 32611 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2005 Summary: (appended verbatim from investigator's abstract): Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy. DM is an autosomal dominant neuromuscular disorder that is caused by a (CTG)n repeat expansion in the 3' UTR of the DM protein kinase (DMPK) gene. The long term objective of the proposed research is to elucidate how a triplet repeat expansion in the 3' UTR of a gene leads to a dominantly inherited disease. Current evidence suggests that DM pathogenesis is associated with the accumulation of DMPK mutant allele transcripts within the nucleus. Our working 'sequestration' hypothesis is that DM is an RNA dominant disease in which the (CUG)n expansion forms an exceptionally stable double stranded RNA (dsRNA) hairpin structure. This unusual RNA hairpin acts as a high affinity binding site for triplet repeat expansion dsRNA binding proteins that possibly play important roles in nucleocytoplasmic RNA export. Large repeat expansions associated with severe disease lead to sequestration of these proteins on DMPK mutant allele transcripts and a dominant negative effect on the export of other RNAs. This proposal is focused on testing this RNA dominance model using several different experimental approaches. First, the hypothesis that (CUG)n expansion RNAs have a dominant negative effect on mRNA export will be directly examined using RNA microinjection into frog oocyte and mammalian fibroblast nuclei. Second, the sequestration hypothesis predicts that expansion binding proteins should accumulate in nuclear foci together with DMPK mutant transcripts. Therefore, we will complete the characterization of several proteins that preferentially recognize large (CUG)n expansions, and determine the subcellular distribution of these proteins in normal and DM patient cells. Third, preferred RNA binding sites for these expansion binding proteins will be characterized by in vitro and in vivo analyses with particular emphasis on identifying RNAs that normally associate with these proteins. Fourth, we will determine if expansion binding proteins are involved in mRNA export by combining the use of monoclonal antibodies and recombinant proteins with the microinjection system developed in the first aim. Fifth, the relevance of RNA dominance to other neuromuscular and neurological diseases will be investigated. These studies have important implications for elucidating molecular mechanisms involved in DM pathogenesis and cellular strategies which facilitate the exchange of genetic information between the nucleus and cytoplasm. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RNA/PROTEIN REGULATION

INTERACTIONS

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PREMRNA

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Principal Investigator & Institution: Singh, Ravinder; Molecular, Cellular & Dev Biol; University of Colorado at Boulder Boulder, CO 80309 Timing: Fiscal Year 2001; Project Start 01-AUG-1999; Project End 31-JUL-2004 Summary: Sex determination is a fundamental decision that essentially all metazoans encounter during their development. Sex determination in Drosophila melanogaster involves a hierarchy of alternative splicing decisions, and is also the best understood

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example of splicing regulation. Splicing is a process by which non-coding sequences (introns) are removed from the precursor messenger RNA. In higher eukaryotes, constitutive and alternative splicing are important aspects of gene regulation in many important cellular processes. Approximately 15 percent of the mutations that have been linked to human diseases affect RNA splicing signals, including cellular transformation, Duchenne muscular dystrophy, and tumor metastasis. Our goal is to understand how RNA-binding proteins recognize target RNAs and regulate constitutive and alternative pre-mRNA splicing. The Drosophila protein Sex-lethal (SXL) acts as a key binary switch between the male and female cell fates. In the past, we defined the mechanism by which SXL regulates alternative splicing by antagonizing the known splicing factor U2AF65. Specificity is an underlying theme in biological regulation. U2AF65 and SXL offer excellent models for specific RNA-protein interactions in the context of splicing regulation. For example, while the general splicing factor U2AF65 recognizes a wide variety of polypyrimidine-tract/3' splice sites, the highly specific splicing repressor SXL recognizes a specific sequence. Although both proteins contain a ribonucleoproteinconsensus motif, they have distinct RNA-binding specificity. However, it is not understood how these seemingly similar proteins achieve unique RNA-binding specificities. To define the structural basis for the RNA-binding specificities of U2AF65 and SXL, we will extend our analysis of the RNA and the proteins by using a combination of biochemical, molecular, and genetic approaches. Our findings will also be directly applicable to other members of this largest family that likely regulate different aspects of RNA biogenesis. In addition, SXL controls many female-specific functions. However, some of the relevant genes that are regulated by SXL remain to be identified. To identify these targets, we will use a combination of recently developed molecular approaches - genomic SELEX and subtractive hybridization/differential display. These approaches should complement genetic analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF ELAV IN NEURONAL RNA PROCESSING Principal Investigator & Institution: White, Kalpana P. Professor; Brandeis University 415 South Street Waltham, MA 024549110 Timing: Fiscal Year 2002; Project Start 10-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): The long-term goal of this research project is to understand how differentially-expressed trans-acting factors in neurons can control premRNA processing to precisely regulate neuronal gene expression. The powerful genetics, molecular biology and transgenic techniques of Drosophila, along with the emergent DNA microarray technology, will be utilized to study the role of ELAV in mRNA processing and its overall impact on gene expression in neurons. ELAV is the founding member of the ELAV/Hu family of RNA-binding proteins, which is conserved in both vertebrates and invertebrates. Members of the ELAV/Hu family serve diverse roles in mRNA processing, including splicing, stability and translatability. The aims of the project are: (1) elucidation of mechanisms of ELAV's interactions with RNA transcripts, (2) identification of direct targets of ELAV using immunoprecipitated ELAVribnucleoprotein complexes and DNA microarrays, (3) assessment of the overall impact of ELAV on gene expression using microarray technology. Together, these approaches will begin to identify networks of genes that are regulated collectively and provide a comprehensive view of how post-transcriptional regulation is utilized in neuronal gene expression. Given the evolutionary conservation between Drosophila and human genomes, insights in regulatory strategies will be directly transferable to human studies. Human members of the ELAV/Hu family have been implicated in pathogenesis of


paraneoplastic cerebellar dysfunction. RNA processing defects have been documented in a large number of human diseases and inherited disorders including cancer, muscular dystrophy and fragile X syndrome. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF THE ALPHA 7 BETA 1 INTEGRIN IN MUSCLE INTEGRITY Principal Investigator & Institution: Kaufman, Stephen J. Professor; Cell and Structural Biology; University of Illinois Urbana-Champaign Henry Administration Bldg Champaign, IL 61820 Timing: Fiscal Year 2001; Project Start 24-JAN-1997; Project End 31-AUG-2006 Summary: (provided by applicant): The proper association of muscle fibers with laminin in the extracellular matrix is essential for normal muscle function. The alpha7Beta1 integrin and the dystrophin-glycoprotein complex both bind laminin and appear to be complementary linkage systems between fibers and the extracellular matrix. Congenital and acquired defects in the dystrophin-glycoprotein complex underlie the pathology associated with Duchenne and other muscular dystrophies, as well as cardiomyopathies. Mutations in the human alpha7 gene cause an additional myopathy. We recently discovered that enhanced expression of the alpha7 integrin mediated linkage system can compensate for the absence of the dystrophin-glycoprotein complex. Dystrophin/utrophin null mice develop an acute muscular dystrophy and die prematurely. Enhanced expression of the alpha7 integrin inhibits the development of muscular dystrophy and restores longevity to these animals. We propose to expand on this result and determine the level of alpha7Beta1 integrin that best prevents development of skeletal muscle pathology in these animals and whether transgene expression in the heart and smooth muscle can prevent cardiovascular disease. We will also analyze whether enhanced expression of the alpha7 integrin in the heart reduces development of cardiomyopathy associated with enterovirus-induced cleavage of dystrophin. Additional skeletal muscle and cardiomyopathies result from other defects in the dystrophin-glycoprotein linkage system. We will use transgenic animals that over-express the alpha7Beta1 integrin in different genetic backgrounds to determine whether the integrin can prevent these myopathies. Whereas mutations in the sarcoglycan genes perturb the dystrophin-glycoprotein transmembrane linkage system and cause cardiomyopathy and muscular dystrophy, we will determine whether overexpression of the alpha7 integrin can inhibit the development of muscle disease in sarcoglycan deficient mice. Likewise, we will assess whether enhanced integrin expression will ameliorate alpha2-laminin congenital muscular dystrophy. Lastly, experiments are proposed that aim at understanding the mechanism by which enhanced integrin expression inhibits development of muscle pathology. This research will reveal whether increasing alpha7 integrin levels in humans may be worth pursuing in the future as treatments for Duchenne and other muscular dystrophies and cardiomyopathies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SARCOLEMMA IN FSHD Principal Investigator & Institution: Bloch, Robert J. Professor; Physiology; University of Maryland Balt Prof School Baltimore, MD 21201 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2004 Summary: (provided by applicant): Facioscapulohumeral Muscular Dystrophy (FSHD) affects 1 of every 20,000 adults in this country. FSHD has been linked to deletions at the

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telomeric region of chromosome 4 (4q35-4q35ter), and is inherited as a dominant trait. Although we have learned a great deal about the genetic defects that lead to FSHD, we still know very little about the effects these defects have at the level of individual muscle fibers. Indeed, the cell biological changes that result in muscle weakness and myofiber degeneration have never been studied. Here we propose to address this issue by examining human biopsied materials using ultrastructural techniques and immunofluorescence coupled with confocal laser scanning microscopy. We postulate that, like other human dystrophies, such as Duchennes, Beckers, and some limb girdle muscular dystrophies, the sarcolemma of FHSD muscle is altered in ways that lead to muscle weakness and ultimately to muscle degeneration. In support of this hypothesis, our preliminary studies show that the sarcolemma of FSHD muscle has frequent interruptions in its membrane skeleton, is separated from the nearest myofibrils by a considerable gap, and is organized irregularly, and most closely resembles the sarcolemma of slow twitch muscle fibers although the myoplasm is rich in fast twitch myosin. We propose to pursue three aims in our exploratory studies of FSHD muscle that will: (i) test the validity of these observations and to extend them, if possible; (ii) compare them to other human muscular dystrophies; and (iii) study the biomechanical properties of the sarcolemma, to learn if they are compromised by FSHD. Our final aim will: (iv) examine the sarcolemma of the myd mouse, which has been proposed as a possible animal model of FSHD. Our laboratory has developed an unique set of methods and antibodies that permit us to examine the overall organization of the sarcolemma and its relationship to the nearby contractile apparatus. In the past year, we have adapted these methods for use with snap frozen biopsies of human skeletal muscle. We therefore anticipate making significant progress in understanding the cell biological changes that occur in FSHD skeletal muscle, and in determining which, if any, of these changes are related to the pathophysiology of FSHD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SATELLITE STEM CELL BIOLOGY Principal Investigator & Institution: Booth, Frank W. Professor; Veterinary Biomedical Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, MO 65211 Timing: Fiscal Year 2001; Project Start 15-APR-2000; Project End 31-MAR-2004 Summary: (Adapted from the applicant's abstract): Satellite cells are muscle-specific stem cells that function to repair damaged myofibers and provide new myonuclei for muscle enlargement. Rosenblatt has shown that knocking out the proliferative capacity of satellite cells prevents hypertrophy of skeletal muscle. Blau and Wright have found that satellite cells prematurely senesce in young patients with Duchenne's muscular dystrophy who have many cycles of regeneration. Schultz has observed a progressive loss of the proliferative capacity of satellite cells as rats age, and similar data has just been reported in humans. Hayflick showed that normal, diploid cells have a finite proliferative lifespan and reach cellular senescence. However, Bischoff indicated that a critical evaluation of the self-maintenance criteria required to categorize the satellite cell as stem cell is yet to be undertaken. These provocative reports highlight some of the conceptual framework to pose the following specific aims. Using the well-established and validated approach of clonogenecity assays to determine a cell's proliferation potential, this proposal examines 1.) whether a physiological model of repeated cycles of atrophy-regrowth in old skeletal muscle speeds satellite cells to senescence so that their proliferative capacity is depleted prior to the lifespan of rats; 2.) determine whether the application of IGF-1 to skeletal muscle or 3.) increased contractile activity, or both aims 1 and 2 results in either a.) using up or b.) replenishing the finite population doublings in


old satellite cells. These results would shed much needed insight into whether replicative senescence can be modulated by environmental factors. The information thus gleaned from these studies will provide the basis for follow-up experiments that will measure cell cycle markers to begin to explain the observations in molecular detail. As the number of individuals with frailty is rapidly increasing, it becomes a more urgent clinical, social, and economic issue to find out if and how satellite cell lifespan can be maintained/enhanced. This proposal will therefore provide novel insights into how the self-maintenance properties of satellite cells is modulated by compensatory factors (IGF1 and exercise), thereby forming the basis for more effective interventions against senileatrophy and frailty. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SFT FUNCTION AND REGULATION IN HEMOCHROMATOSIS Principal Investigator & Institution: Wessling-Resnick, Marianne; Professor; Nutrition; Harvard University (Sch of Public Hlth) Public Health Campus Boston, MA 02460 Timing: Fiscal Year 2001; Project Start 15-SEP-1999; Project End 31-AUG-2004 Summary: Hereditary hemochromatosis is a genetic disorder that promotes increased intestinal absorption and progressive tissue deposition of iron resulting in cirrhosis of the liver, hepatic carcinoma, congestive heart failure, endocrinopathies and premature death. It is estimated that 1 in 200-to-400 people in the US are homozygous for this disease which is the most common defective genetic trait known in humans, more prevalent than cystic fibrosis, phenylketonuria and muscular dystrophy combined. Iron assimilation is a tightly regulated process that is limited to prevent harmful effects due to overload of this toxic metal and therefore a reciprocal relationship exists between body iron stores and dietary iron absorption, although the molecular basis for ion homeostasis remains unknown. Many studies of the molecular basis for hemochromatosis have evaluated the expression of factors involved in iron metabolism , including transferrin, transferrin receptor, ferritin and IRPs, but strong evidence to support their abnormal regulation in this disease is lacking. We recently identified SFT (Stimulator of Fe Transport) as a facilitator of non-transferrin-bound iron uptake. Our preliminary results demonstrate that SFT expression is down- regulated at both the mRNA and protein level in response to iron-loading. However, in the course of these studies, we made the significant discovery that SFT mRNA is 5-fold higher in liver from hemochromatosis patients despite the deposition of iron that occurs in this tissue. Thus, our working hypothesis is that malregulated expression of SFT contributes to the etiology of hemochromatosis. The proposed research will specifically evaluate our hypothesis through the following goals: 1) determination of SFT activity in iron transport by hepatocytes and intestinal enterocytes; 2) examination of interactions of interactions with the hemochromatosis protein Hfe that may modulate SFT expression and function in these cells; and 3) characterization of the mechanism that regulates SFT expression. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SIGNAL TRANSDUCTION MECHANISMS IN THE NERVOUS SYSTEM Principal Investigator & Institution: Chao, Moses V. Professor; Cell Biology; New York University School of Medicine 550 1St Ave New York, NY 10016 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2004

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Summary: This application is for a new training program in the mechanisms of signal transduction in the nervous system at New York University Medical Center. The training faculty include fifteen distinguished scientists representing the Departments of Physiology and Neuroscience, Pharmacology, Microbiology Biochemistry and Cell Biology. The research interests of the program faculty encompass a broad range of fields, including growth factors, cytokines, chemokines, neurotrophic factors and the mechanisms by which extracellular and intracellular signals are transduced; cell adhesion molecules that influence neuronal axonal pathfinding and process outgrowth; selection of synaptic targets; ion channel function; and processes that lead to axonal-glial cell communication. The purpose of this program is to foster the training of graduate students and postdoctoral fellows in basic mechanisms by which neuronal, glial and neuromuscular structure and function are determined. The underlying theme of the program is that cell specification and function in the nervous system are dependent upon ligand-receptor interactions and activation of second messenger pathways. Based upon a record of productive interactions, research collaborations among the trainees and between the participating faculty will be fostered. Trainees will participate in activities including weekly seminars and journal clubs in cellular and developmental neurosciences, journal clubs, and meetings that are designed to provide a broad educational exposure. The emphasis in this training program will be on fundamental biochemical and cellular mechanisms, which are relevant to disorders of the nervous system, including Alzheimer's disease, Parkinson's disease, paralysis, multiple sclerosis and muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SK CHANNELS IN HYPEREXCITABLE SKELETAL MUSCLE Principal Investigator & Institution: Adelman, John P. Senior Scientist; None; Oregon Health & Science University Portland, OR 972393098 Timing: Fiscal Year 2001; Project Start 01-APR-1998; Project End 31-MAR-2002 Summary: Skeletal muscle excitation is normally controlled by the influence of innervating nerve. However, prior to innervation, upon denervation, in patients with myotonic muscular dystrophy (DM), or myotubes cultured in the absence of nerve, skeletal muscle is hyperexcitable, in that a train of action potentials is often induced following an evoked contraction. The cellular hallmark of these conditions is the appearance of receptors for the peptide toxin apamin, a potent blocker of small conductance calcium-activated potassium (SK) channels. Indeed, application of apamin to denervated or myotonic dystrophic skeletal muscle dramatically repress the hyperexcitability, demonstrating that SK channels are central to the hyperexcitable state. We have cloned the apamin sensitive SK channels from skeletal muscle, SK3, and found that upon denervation or after differentiation of the muscle cell line, L6, the SK3 gene is expressed while in normally innervated muscle it is not expressed. Neither the physiological role of SK channels in hyperexcitable skeletal muscle nor the molecular cues controlling SK3 gene expression are yet understood. In this proposal, we will test the hypothesis that: (1). SK3 channels reside in the transverse tubules of denervated skeletal muscle cells. Patch clamp measurements will be performed using denervated normal and detubulated cultured myotubes. Immunohistochemistry using SK3 channelspecific antibodies, and I125-apamin binding studies will be performed. (2). SK channel activity induces hyperexcitability. Skeletal muscle myotubes and nerve cells will be cocultured. SK channels will be heterologously expressed by infection with recombinant retroviruses and the cells electrophysiologically assayed. (3). The SK3 promotor is activated following differentiation of cultured L6 myoblasts. a) SK3 promotor/luciferase


constructs will be introduced into L6 myoblasts, and luciferase activity assessed before and after differentiation; b) gel-shift and footprint assays will be performed with nuclear extracts from pre- and post-differentiated L6 cells; c) previously uncharacterized sequences in the SK3 promotor shown to be necessary for activation following myoblast differentiation will be used to screen a differentiated L6 skeletal muscle cDNA expression library. (4). DMAHP (myotonic dystrophy associated homeodomain protein or DMPK (myotonic dystrophy protein kinase) regulates SK channel expression. a) DMAHP and/or DMPK will be ectopically expressed in L6 myoblasts and SK3 mRNA and channel activity assessed before and after differentiation. b) gel-shift assays and footprints will be performed with the SK gene promotor and recombinant DMAHP; c) SK3 promoter/luciferase constructs will be introduced with or without DMAHP and/or DMPK into L6 myoblasts and the promoter elements responsible for regulation will be determined. These studies will establish a framework for understanding the molecular, cellular and physiological abnormalities of hyperexcitable skeletal muscle as well as the coordinate regulation of SK gene expression in muscle tissue. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SKELETAL MUSCLE STRUCTURE AND FUNCTION IN AGING MDX MICE Principal Investigator & Institution: Brooks, Susan V.; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, MI 481091274 Timing: Fiscal Year 2001 Summary: The purpose is to investigate the function of dystrophin and the dystrophinassociated proteins (DAPs) in skeletal muscle fibers and how defects in the dystrophinDAP complex contribute to the pathological changes in muscle over the life span of mdx mice. The absence of dystrophin from the muscles of patients with Duchenne muscular dystrophy leads to ongoing muscle fiber degeneration, progressive necrosis, and fibrosis. Dystrophin is also absent from the muscles of mdx mice. The mechanisms underlying the degenerative process in dystrophic muscle are unknown, but replacement of dystrophin in transgenic-mdx mice prevents many of the dystrophic symptoms. In control animals, degeneration of myofibers may result from contractioninduced injury and susceptibility to contraction-induced injury than those in agematched control mice, but for muscles in transgenic-mdx mice the susceptibility to injury is not known, nor has the effect of age on contraction-induced injury been studied in mdx or transgenic mdx-mice. The working hypothesis are that (i) the dystrophin-DAP complex shunts contractile forces laterally from the myofibrils through the plasma membrane to the extracellular matrix, and a lack of dystrophin results in stress concentrations on the sarcolemma which damage the membrane, and a mechanically compromised cytoskeleton which increases sarcomere heterogeneity and damage; and (ii) the increased susceptibility to both sarcolemma and sarcomere damage is aggravated as animals age. Specific hypotheses have been formulated regarding the mechanical function of dystrophin and the effects of age on contraction- induced injury of dystrophic muscle fibers. Structure/function relationships of the dystrophin-DAP complex will be studied in single intact fibers from muscles of control, mdx, and transgenic-mdx mice, and contraction-induced injury will be studied using single fibers in vitro and whole muscles in situ from adult and old mice. Determining the function of dystrophin and why its absence is so devastating will contribute significantly to out understanding of the mechanisms underlying the wasting and weakness that occurs with dystrophy and with normal aging. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SPIRITUALITY OF CHILDREN WITH DMD Principal Investigator & Institution: Pehler, Shelley-Rae; None; University of Iowa Iowa City, IA 52242 Timing: Fiscal Year 2003; Project Start 14-MAR-2004 Summary: (provided by applicant): This application proposes research to explore the spirituality of an 8 -12 year old child with Duchenne Muscular Dystrophy. Duchenne Muscular Dystrophy (DMD) is a progressive, genetically inherited, chronic disease with a life-threatening prognosis. Early confirmation of the type of genetic disease a child has allows interventions to be initiated that may affect the quality and longevity of life. What is not known is the spirituality of children with a genetically inherited, life threatening disease, even though the literature is clear that there is a heightened spirituality in the adult and adolescent populations with similar diseases. This heightened spirituality has provided meaning to the adult and adolescents' life to promote healing. Healing does not mean cure in the usual use of the word, but instead a sense of health and well-being as experienced by hope, love, sense of control, relatedness with others, finding meaning and purpose in life and disease, and a sense that there is something greater than the self (Fryback, 1993; Mytko & Knight, 1999). The purpose of this study is to explore spirituality in children who are 8 -12 years of age and who have been diagnosed with the genetic, life-threatening disease of Duchenne Muscular Dystrophy. Giorgi's (1985) qualitative design will be used for this phenomenological study. Children 8 -12 years old with DMD will be recruited from a large, mid-western genetics clinic. Children will be invited to participate in the research until no new themes or meaning units are identified during the interviews. Interviews using open-ended questions and descriptions by the children of drawings they have made will elicit the data. Interview data will be transcribed to sheets of paper verbatim. Demographic information will be used to generate descriptive statistics for the sample population and to determine any religious belief systems that would help in the understanding of the child's responses to the questions. Analysis of the data will follow Giorgi's (1985) method of analysis. Rigor will be addressed through bracketing prior to interviewing and data analysis, using two different data collection strategies, development of a detailed Interview Schedule, using a peer debriefed, and developing an audit process for field notes and data analysis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: STRUCTURE/FUNCTION OF CH DOMAIN PROTEINS Principal Investigator & Institution: Matsudaira, Paul T. Professor of Biology and Bioengineering; Whitehead Institute for Biomedical Res Biomedical Research Cambridge, MA 02142 Timing: Fiscal Year 2001; Project Start 01-MAY-1998; Project End 30-JUN-2002 Summary: The Calponin-Homology (CH) domain identifies a new super family of cytoskeletal proteins that integrate the cytoskeleton and signalling pathways. Based on a small actin binding domain from calponin, the CH domain functions as a module that targets various proteins including signaling proteins, vav and IQGAP, and actin crosslinking proteins to actin filaments. More recently, CH domains were discovered in the IFAPs plectin and BPAB1n1 (dystonin) suggesting that they connect the actin and intermediate filament cytoskeletons. This widespread use of CH domains in important structural and signaling systems may provide a direct cellular mechanism for regulating cell structure. To understand how CH domain proteins organize the cytoskeleton, this proposal has three specific aims. The first goal is to describe the mechanism of cross


linking by fibrin by determining the 3D structure of a fimbrin-actin cross link and by identifying interacting residues at the binding interface by site directed mutagenesis. This structure will serve as a model for understanding how CH domain proteins bind the actin cytoskeleton. The second aims to describe the function of the fibrin-vimentin complex at cell substratum adhesion sites. Interactions between the actin and IF cytoskeleton may play in important role in the assembly and/or stability of a cell attachment. The last aim is to identify the function of calponin by a combination of biochemical and genetic approaches. In the simple cytoskeleton of yeast which lacks the muscle contractile system, calponin should more closely represent its function in nonmuscle cells. The applicant points out that studies on CH domain proteins are directly relevant to understanding underlying mechanisms of disease. The oncogenic properties of vav, the onset of myotonic dystony, blood disorders, and muscular dystrophy are caused by defects in different members of the CH domain superfamily. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE-FUNCTION ANALYSIS OF SARCOSPAN Principal Investigator & Institution: Crosbie, Rachelle H. Duchenne Musc Dyst Res Ctr; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 24-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): The broad, long-term objectives of this proposal are to understand the structure and function of a novel tetraspanin called SARCOSPAN. Sarcospan is an integral component of the dystrophin-glycoprotein complex and is highly expressed in skeletal and cardiac muscles, as well as many non-muscle tissues (Crosbie et al., 1997; Crosbie et al., 1998; Crosbie et al., 1999). The dystrophinglycoprotein complex (DGC) is a structural complex that spans the muscle plasma membrane and links the extracellular matrix with the intracellular cytoskeleton. This structural linkage is critical for normal muscle function as clearly demonstrated by the many forms of muscular dystrophy that result from mutations in the dystrophinglycoprotein complex. Association of several signaling molecules with the DGC also suggests that this complex may play a role in mediating extracellular-intracellular communications. Furthermore, lateral associations amongst membrane components of the DGC are critical for function of this complex. It is hypothesized that sarcospan facilitates protein-protein interactions within the dystrophin-glycoprotein complex. These protein interactions are clearly important for the physical linkage between the extracellular matrix and the intracellular actin network and for the prevention of muscular dystrophy. Human mutations within the sarcospan gene have not been identified in known cases of autosomal recessive muscular dystrophy (Crosbie et al., 2000). However, these mutation searches have only examined the ubiquitous form of SSPN, which has a broad expression pattern. Preliminary data demonstrates that a novel, muscle-specific form of SSPN is expressed in skeletal and cardiac muscles. We hypothesize that mutations within muscle-SSPN may cause novel forms of muscular dystrophy. Identification and characterization of this muscle-sarcospan will advance our understanding of the role of the dystrophin-glycoprotein complex in normal muscle and in the pathogenesis of muscular dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SURGICAL APPROACHES TO SYSTEMIC GENE TRANSFER Principal Investigator & Institution: Stedman, Hansell H. Assistant Professor; Surgery; University of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104

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Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): The overall aim of the proposed research is to improve the prospects for therapeutic gene transfer in Duchenne muscular dystrophy by addressing two essential rate-limiting issues: immunity to the transgene product and vector delivery. Using a newly described canine animal model for Duchenne muscular dystrophy, the German Short Haired Pointer, the experimental design takes advantage of a deletion of the dystrophin gene to evaluate the comparative immunogenicity of dystrophin and utrophin. We make exclusive use of rAAV vectors. The experimental design tests the hypothesis that in the context of the deletion, recombinant (canine) mini-dystrophin will elicit a deleterious cellular immune response. It further tests the hypothesis that substitution of a similarly designed canine mini-utrophin transgene will circumvent this immune response. Based on extensive preliminary data, the proposal also addresses the hypothesis that the endothelial barrier to systemic gene delivery can be bypassed by temporarily infusing histamine during a period of mechanical circulatory support. We propose a graded series of experiments to address the latter hypothesis, starting with isolated limb perfusion and culminating in systemic gene delivery. These studies will also make extensive use of another naturally occurring animal model, the hamster model for limb-girdle muscular dystrophy. Successful completion of the experimental plan will provide general information relevant to the immunological response to somatic gene delivery and the preservation of organ function during profound but rapidly reversible alterations in endothelial integrity. It will also provide specific information about the rational design of strategies for systemic gene therapy in one of the most common single-gene lethal diseases in man, Duchenne Muscular Dystrophy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYMPATHETIC ACTIVITY AND OXYGENATION IN SKELETAL MUSCLE Principal Investigator & Institution: Victor, Ronald G. Associate Professor; University of Texas Sw Med Ctr/Dallas Dallas, TX 753909105 Timing: Fiscal Year 2001 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TESTING MOLECULAR MODELS OF SPECTRIN FLEXIBILITY Principal Investigator & Institution: Macdonald, Ruby I. Biochem/Molecular & Cell Biol; Northwestern University 633 Clark St Evanston, IL 60208 Timing: Fiscal Year 2001; Project Start 01-JAN-1998; Project End 30-JUN-2005 Summary: (provided by applicant): The long-term objective of this proposal is to understand the molecular basis of flexibility of the ubiquitous cytoskeletal protein, spectrin, and its relatives, alpha-actinin and dystrophin. Continuing the previously successful strategy of determining the X-ray crystal structure of two connected repeating units of chicken brain alpha-spectrin, which led to the proposal of two of the first molecular models of spectrin flexibility, a follow-up investigation is proposed to critically test those models. The strengths of X-ray crystallography, fluorescence and nuclear magnetic resonance (NMR) spectroscopy will be exploited to address the following important questions about the models: 1) Is the conformation of a linker region coordinated with that of an adjacent linker region in a three repeat fragment? 2) Are linker regions predicted to be a random coil by secondary structure prediction


methods nonhelical (which, if true, could suggest yet a third model of spectrin flexibility and also offer the possibility of studying mutations correlated with hereditary elliptocytosis)? 3) How does the absence of the nearly invariant tryptophan affect the conformation of the linker region and flexibility of two connected repeats? 4) Is conformational rearrangement of one of the previously determined structures-a key feature of one of the models--due to the phasing or to the sequence of the construct? To answer these crucial questions concerning models of spectrin flexibility, 3 structures will be determined by X-ray crystallography, 2 will be studied by fluorescence energy transfer and 10 will be analyzed by NMR. These three approaches will complement each other as the X-ray crystal structures will provide atomic distances for interpretation of energy transfer data and vector orientations for interpretation of NMR data, and energy transfer and NMR data will provide dynamic information about the crystal structures. The cloned spectrin fragments will also be characterized by their circular dichroism and fluorescence spectra, by their stabilities to urea and thermal denaturation and by their molecular weights on analytical ultracentrifugation. Proposed critical testing of molecular models of spectrin flexibility will contribute fundamental knowledge likely to advance understanding of conditions such as hereditary elliptocytosis and spherocytosis, muscular dystrophy, hydrops fetalis and Fanconi anemia, in all of which spectrin or spectrin-related proteins are abnormal or reduced in amount. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE NEW STEM CELL BIOLOGY Principal Investigator & Institution: Quesenberry, Peter J. Chief, Research Department; Roger Williams Hospital 825 Chalkstone Ave Providence, RI 02908 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): This COBRE grant has 4 major objectives: 1.) The development of a strong mentoring group of established investigators; 2.) The enhancement of infrastructure support through the development of core laboratories, administrative support, and resources; 3.) The recruitment and retention of young and established faculty at Roger Williams Medical Center (RWMC) and collaborating Providence institutions (Brown, Miriam Hospital, and Rhode Island Hospital) in order to continue the establishment of a major stem cell research center for the state, region, and country; and 4.) To define the capacity of marrow cells to produce skin and muscle cells, and to define the clinical potential of these approaches in murine wound healing and muscular dystrophy models, and to establish Vector Systems to use siRNA to inhibit stem cell transcriptional pathways and to assess the effect on the stem cell phenotype, beginning with PU.1. We have assembled an experienced group of scientists who will mentor 3 promising young investigators and are prepared to mentor others in different research areas. The work is thematically coordinated around stem cell biology and plasticity and transcriptional regulation of stem cells and the potential for using siRNA to redirect stem cell differentiation. The 3 projects and their P.I.s are: Project 1 Dr. Evangelos Badiavas - studies on the capacity of marrow cells to transdifferentiate (or convert) to skin cells and heal wounds. Project 2 - Dr. Mehrdad Abedi - the capacity of marrow cells to produce skeletal muscle cells and treat muscle disorders. Project 3 - Dr. Bharat Ramratnam - Stem cell gene modulation by RNAi. These scientific projects are supported by an Administrative Core, A Cell Sorter/Flow Cytometry Clore, and a Cell Phenotyping Core. Plans are outlined for continued mentoring of junior P.l.s, and specific approaches for evaluating the progress of the P.I.s. and a plan to specifically guide the P.l.s to RO1 funding is included. Institutional commitment is strong and not dependent on COBRE funding. Plans are also outlined for the recruitment and

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development of new junior faculty to the institutions and COBRE. The award of COBRE application would effectively facilitate the continued development of Center for Stem Cell Biology. This grant also has real promise in expanding understanding of stem cell plasticity and stem cell transcriptional regulation developing pre-clinical models for wound healing and muscular dystrophy.

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Project Title: THE ROLE OF DYSTROGLYCAN IN SIGNAL TRANSDUCTION Principal Investigator & Institution: Ruohola-Baker, T H. Associate Professor; Biochemistry; University of Washington Seattle, WA 98195 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Dystroglycan (DG) is a key element of the dystrophin associated glycoprotein complex (DGC), which is closely linked to pathogenesis of several forms of muscular dystrophy. However, the basic cellular function of this DG complex is largely unknown. The overall objective of this project is to study the protein-protein interactions in which DG is involved in and their implications for cellular signaling. The extracellular matrix and cytoskeletal network are intricately interconnected, providing the cell with both structural integrity and a means for signal transduction. As a transmembrane protein, DG provides a physical link between the extra cellular matrix and cytoskeleton by attaching to laminin-2 at its Nterminus and to the cytoskeletal protein dystrophin at its C-terminus. Recent evidence has implicated DG in cellular signaling processes by binding to SH2/SH3 domain containing proteins, but the downstream signaling pathways are not clearly understood. To advance the understanding of DG's role in cellular signaling, this research aims to address the questions below in vitro and in vivo in Drosophila. 1) What is the biochemical basis of selective DG binding to Dystrophin, Grb2 and Src? 2) What is the functional significance of this selective binding? 3) What molecules, other than Dystrophin, Grb2 and Src interact with DG? We have recently isolated mutations in the DG gene and showed that DG is required for establishing the polarity in both the oocyte and the epithelial cell layers. By combining known biochemical data from mammalian systems with the advantages of Drosophila genetics and modern quantitative biochemistry we will dissect the functional role of differential protein binding by DG and identify new signaling molecules interacting with DG. In the future, we will investigate the developmental functions of DG associated signaling molecules. This research will advance the understanding of DG function in signal transduction and how it is regulated to mediate different intracellular pathways. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE ROLE OF NUCLEAR LAMINS IN MUSCLE DISEASE Principal Investigator & Institution: Burke, Brian; Professor; Anatomy and Cell Biology; University of Florida Gainesville, FL 32611 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAR-2007 Summary: (provided by applicant): A-type and B-type nuclear lamins form a family of nuclear envelope proteins that have an essential function in the maintenance of nuclear structure. Mutations in the human lamin A gene have been linked to several diseases which include Emery-Dreifuss muscular dystrophy (EDMD) and cardiomyopathy. Since the A-type lamins are found in majority of adult cell types it is extremely puzzling that defects in these proteins should be associated primarily with muscle specific disorders. The goal of this proposal is to elucidate the roles that individual lam in family


members play in the organization of the cell nucleus and how in particular this relates to the maintenance of muscle integrity. The proposal will take advantage of mouse strains harboring targeted mutations in lamin genes, including a strain in which the lamin A gene has been deleted and which develops a disorder that closely resembles human EDMD. Inactivation of B-type lamin genes as well as the introduction of specific human disease-linked point mutations into the mouse lamin A gene will provide novel insight into the role of individual lamin proteins in nuclear organization and how this relates to disease processes in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THERAPEUTIC APPROACHES FOR MUSCULAR DYSTROPHY Principal Investigator & Institution: Spencer, Melissa J. Assistant Professor; Duchenne Musc Dyst Res Ctr; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, CA 90024 Timing: Fiscal Year 2001; Project Start 05-MAY-2000; Project End 30-APR-2005 Summary: (appended verbatim from investigator's abstract): Duchenne muscular dystrophy (DMD) is the most common, inherited, lethal disease of childhood. Despite its high frequency of occurrence and the extensive knowledge of the molecular genetics of DMD, the lifespan or quality of life of DMD children has not improved over that which existed before the mutant gene was discovered approximately 13 years ago. Recently, our laboratories have shown that the histologically discernible pathology of the muscles of mdx mice, the most widely used animal model of the disease, could be reduced by more than half through interventions that inhibit cytotoxic T lymphocytes (CTLs). This is the greatest systemic improvement in the pathology of dystrophic muscle attained by any intervention, and it indicates that important new avenues for approaching DMD therapeutics may exist. The general goal of the investigation proposed here is to obtain more specific information concerning the role of T Iymphocytes in the death of dystrophic muscle, so that more specific therapeutic interventions with applicability to humans can be developed in future work. This will be done by: 1) determining whether distinct populations of T lymphocytes function through independent mechanisms in the autoreactive killing of mdx muscle, 2) testing whether binding of costimulatory molecules that are involved in Tcell activation is important for activation of autoreactive Tcells in mdx mice, and whether simultaneous blockade of these molecules is maximally effective for treatment, 3) testing whether the blockade of costimulating molecu1es of Tcells in mdx mice is most effective at reducing muscle pathology when applied early in the disease process, and 4) testing whether treatment of utrophin deficient mdx mice through Tcell depletions or with blockers of Tcell costimulation is effective in reducing muscle pathology and extending lifespan. Collectively, these findings can provide the basis for design of immune interventions to reduce the pathology of dystrophin deficient muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Principal Investigator & Institution: Griggs, Robert C. Professor and Chair; University of Rochester Orpa - Rc Box 270140 Rochester, NY 14627 Timing: Fiscal Year 2001 Summary: To characterize the effect of corticosteroids on muscle protein metbolism in Duchenne dystrophy by studying whole body and muscle protein synthesis, muscle

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mass, and lean body mass. To determine if prednisone administration provokes changes in levels of hormones that might have a net anabolic effect on muscle. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THIN FILAMENTS AND MUSCLE REGULATION Principal Investigator & Institution: Lehman, William J. Professor; Physiology and Biophysics; Boston University Medical Campus 715 Albany St, 560 Boston, MA 02118 Timing: Fiscal Year 2003; Project Start 30-SEP-1986; Project End 30-NOV-2007 Summary: (provided by applicant): Thin filament-associated actin-binding proteins control both actomyosin-based contractility and cytoskeletal formation in muscle and non-muscle cells. To elucidate these mechanisms, it is crucial to determine the structural interactions of the proteins involved. We address several interrelated questions fundamental to understanding muscle thin filament function: (1) What is the architecture of the thin filament in skeletal, cardiac and smooth muscles? (2) What are the changing structural interactions of thin filament-linked proteins that regulate muscle activity? (3) How do these proteins interact with actin to form the muscle cytoskeleton? We use state-of-the-art electron microscopy, image analysis and 3-D reconstruction to establish he macromolecular structure of components bound on thin filament actin. Using these techniques: (A) We aim to determine the structural basis of troponintropomyosin regulation of skeletal and cardiac muscle activity by analyzing interactions of tropomyosin and troponin on thin filaments and the effects of Ca2+ and myosincrossbridge binding. (B) To help understand the organization of the cortical actin cytoskeleton of muscle cells, we aim to determine the structural interactions of dystrophin and utrophin with filamentous F-actin by examining the binding of their distinct calponin homology (CH)-domains. (C) We aim to assess the structural role of thin filament associated caldesmon as a possible modulator of actomyosin-based motility and cytoskeletal assembly in smooth muscle. (D) Studies of the structure of nebulin bound to actin will be part of our continuing investigation of the functional design of thin filaments. In each study, reconstructions will be fitted to the atomic resolution maps of F-actin to define molecular contacts of binding proteins with actin. Further, such "hybrid crystallography" will be used to fit newly solved crystal structures of troponin, tropomyosin, dystrophin and utrophin domains within EM density maps to attain near atomic resolution. Our ongoing studies on troponin-trepomyosin regulated filaments will lead to an elucidation of the molecular mechanism of relaxation and activation in skeletal and cardiac muscle. Our successfully initiated structural studies on utrophin and dystrophin will establish their unique features as cytoskeletal elements, information applicable to designing genetic therapies for muscular dystrophy. Studies on smooth muscle filaments will contribute to understanding the fine-tuning of the smooth muscle contractile response. Such modulation affects vascular tone and pulmonary airway resistance, determinants in, e.g., hypertension and asthma. The wider significance of our goals is underscored by the role of actin and associated proteins in diverse and vital cellular mechanisms that can become aberrant in malignancy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: TRAINING PROGRAM IN THE NEUROSCIENCES Principal Investigator & Institution: Llinas, Rodolfo R. Chairman; Physiology and Neuroscience; New York University School of Medicine 550 1St Ave New York, NY 10016 Timing: Fiscal Year 2001; Project Start 01-JUL-2000; Project End 30-JUN-2005


Summary: (ADAPTED FROM THE APPLICANT'S ABSTRACT): This application is for a new, broad based neuroscience program at the New York University School of Medicine. The training faculty includes 28 distinguished neuroscientists representing the Departments of Cell Biology, Neurology, Neurosurgery, Ophthalmology, Pharmacology, and Physiology & Neuroscience. The diverse research interests of the program faculty include molecular neurobiology, developmental genetics, synaptogenesis, neuron and glial cell structure and function, signal transduction, ion channel and receptor function, motor and sensory systems, brain imaging and cognition. This program will provide solid, broad based training of predoctoral students, with the overall goal to produce competitive, skillful neuroscientists positioned to make significant and diverse contributions to the field. Towards this goal, trainees will participate in a number of core and advanced courses, weekly seminars, journal clubs and tutorials that are designed to ensure broad exposure in the neurosciences. Research collaborations between trainees and participating faculty will be fostered through initial laboratory rotations followed by mentoring of dissertation studies by individual faculty members. The basic and clinical neuroscientists that make up the program faculty will emphasis training relevant to disorders of the nervous system such as Alzheimer's, multiple sclerosis, Parkinson's, muscular dystrophy, Tay-Sachs, stroke and spinal cord injury. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRANSLATIONAL RESEARCH IN THE DYSTROPHINOPATHIES Principal Investigator & Institution: Flanigan, Kevin M. Associate Professor; Neurology; University of Utah 200 S University St Salt Lake City, UT 84112 Timing: Fiscal Year 2002; Project Start 20-SEP-2002; Project End 31-JUL-2005 Summary: (provided by applicant): Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) are devastating disorders. Both are associated with mutations in the dystrophin gene, a huge gene with 79 exons spread over 2.4 million bases of genomic sequence. Deletions of large portions of the gene account for around 60% of all dystrophin mutations. The remainder consist of point mutations (primarily premature stop codon mutations), small deletions resulting in shift of the reading frame, and (in less than 5%) duplications. Dystrophin gene deletion testing is commercially and readily available, but point mutation testing is not. Recent studies in the mdx mouse, a model for DMD due to a premature stop codon mutation, have demonstrated the ability of aminoglycosides to increase the expression of dystrophin protein via induction of increased read-through. Recently, we and others have demonstrated some rules for the specificity of this effect, and a growing body of data suggests that aminoglycoside therapy may prove beneficial in some patients. We have developed the methodology to rapidly, robustly, and economically perform direct sequence analysis of the entire coding and regulatory regions of the dystrophin gene, greatly expediting the characterization of mutations in non-deleted dystrophinopathy patients. Using this methodology, we propose to characterize the mutations responsible for DMD and BMD in a large cohort of patients, from whom a standardized and thorough phenotypic characterization, will be obtained. Phenotype/genotype information will be compiled in a pilot dystrophinopathy registry database. Correlation of the phenotype to the sequence context of specific individual mutations will generate hypotheses of aminoglycoside-induced read-through efficiency in specific sequence contexts, which will be tested in an in vitro dual-luciferase transfection assay. This same assay will be used to systematically study other pharmaceutical compounds, which may cause readthrough of premature stop codon or frameshift mutations, and to study other potential

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mechanisms for modifying intrinsic frame shifting and read-through. Finally, we propose to develop a dual-GFP transgenic mouse, which will allow in vivo characterization of tissue-specific variation in aminoglycoside-induced read-through. Although we do not propose to perform an aminoglycoside treatment trial at present, this proposed study will identify a cohort of patients who may be candidates for any future trials here or at other institutions, and may provide a rationale to suggest that individual compounds or dosages may need to be tailored to specific sequence variations in all future trials. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: TRI-NUCLEOTIDE REPEAT AND FRAGILE SITES IN YEAST Principal Investigator & Institution: Zakian, Virginia A. Harry C. Weiss Professor in the Life Sci; Molecular Biology; Princeton University 4 New South Building Princeton, NJ 085440036 Timing: Fiscal Year 2001; Project Start 29-APR-1998; Project End 28-FEB-2003 Summary: (adapted from investigator's abstract): An ever-increasing number of human genetic diseases are attributed to expansion of trinucleotide repeats (TNRs). For example fragile X syndrome, the second leading cause of mental retardation, is due to expansion of a CGG tract and myotonic muscular dystrophy, is due to expansion of a CTG tract. Moreover, expansion of CGG tracts induce breakage at five known human chromosomal loci, some of which correlate with human disease. Chromosome breakage at fragile site is also implicated in the chromosomal rearrangements characteristic of human tumors. TNRs associated with human disease are rare. TNR and fragile site research would be greatly aided by genetic assays for tract expansion and/or chromosome fragility. The goal of this grant is to develop Saccharomyces cerevisiae as a model for TNR expansion and triplet-mediate chromosome fragility. The investigator has inserted 130 repeats of CTG onto a yeast chromosome. Large expansion of this tract were obtained, the first large expansion reported outside of humans. CTG tracts may also be length-dependent fragile sites in yeast. This observation provides the basis for a simple, genetic assay for tract expansion and chromosome fragility. The assays will be used to identify yeast and human genes whose mutation or over-expression increases CTG expansion and/or fragility. A premise of the proposed work is that most genes that affect TNR stability will encode proteins involved in replication, repair, or chromatin structure, many of which are conserved from yeast to humans. The behavior of CGG tracts will also be studied. Nucleases and DNA methylases will be used to analyze the chromatin structure of CTG and CGG tracts as both DNAs display unusual nucleosome forming properties in vitro. Finally, fragile sites are thought to be caused by late replication of TNR DNA. This model will be tested using density transfer and twodimensional gel electrophoresis to determine if replication timing or replication fork progression is affected by the presence of TNRs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: VENTRICULAR DYSFUNCTION/NEUROHUMORAL ACTIVATION-DMD Principal Investigator & Institution: Zimmerman, Frank; Washington University Lindell and Skinker Blvd St. Louis, MO 63130 Timing: Fiscal Year 2001 Summary: There is no text on file for this abstract. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen


E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “muscular dystrophy” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for muscular dystrophy in the PubMed Central database: •

A 71-Kilodalton Protein is a Major Product of the Duchenne Muscular Dystrophy Gene in Brain and Other Nonmuscle Tissues. by Lederfein D, Levy Z, Augier N, Mornet D, Morris G, Fuchs O, Yaffe D, Nudel U. 1992 Jun 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=49288

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A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy. by Burton EA, Tinsley JM, Holzfeind PJ, Rodrigues NR, Davies KE. 1999 Nov 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24184

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Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. by Wang B, Li J, Xiao X. 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17641

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Altered phosphorylation and intracellular distribution of a (CUG) n triplet repeat RNA-binding protein in patients with myotonic dystrophy and in myotonin protein kinase knockout mice. by Roberts R, Timchenko NA, Miller JW, Reddy S, Caskey CT, Swanson MS, Timchenko LT. 1997 Nov 25; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24290

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Brain dystrophin-glycoprotein complex: Persistent expression of beta-dystroglycan, impaired oligomerization of Dp71 and up-regulation of utrophins in animal models of muscular dystrophy. by Culligan K, Glover L, Dowling P, Ohlendieck K. 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29067

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Detection of Dystrophin in the Postsynaptic Density of Rat Brain and Deficiency in a Mouse Model of Duchenne Muscular Dystrophy. by Kim T, Wu K, Xu J, Black IB. 1992 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=50609

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Expansion of a CUG trinucleotide repeat in the 3[prime prime or minute] untranslated region of myotonic dystrophy protein kinase transcripts results in

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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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nuclear retention of transcripts. by Davis BM, McCurrach ME, Taneja KL, Singer RH, Housman DE. 1997 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23831 •

Fission yeast orb6, a ser /thr protein kinase related to mammalian rho kinase and myotonic dystrophy kinase, is required for maintenance of cell polarity and coordinates cell morphogenesis with the cell cycle. by Verde F, Wiley DJ, Nurse P. 1998 Jun 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=22672

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Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. by Sander M, Chavoshan B, Harris SA, Iannaccone ST, Stull JT, Thomas GD, Victor RG. 2000 Dec 5; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=17659

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Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. by Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, Roberts R, Caskey CT, Swanson MS. 1996 Nov 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=146274

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Intermolecular and Intramolecular Interactions Regulate Catalytic Activity of Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinase [alpha]. by Tan I, Seow KT, Lim L, Leung T. 2001 Apr 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=86907

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Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation. by Gussoni E, Bennett RR, Muskiewicz KR, Meyerrose T, Nolta JA, Gilgoff I, Stein J, Chan YM, Lidov HG, Bonnemann CG, von Moers A, Morris GE, den Dunnen JT, Chamberlain JS, Kunkel LM, Weinberg K. 2002 Sep 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151133

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Molecular Basis for Impaired Muscle Differentiation in Myotonic Dystrophy. by Timchenko NA, Iakova P, Cai ZJ, Smith JR, Timchenko LT. 2001 Oct 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=99869

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Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinase Acts as a Cdc42 Effector in Promoting Cytoskeletal Reorganization. by Leung T, Chen XQ, Tan I, Manser E, Lim L. 1998 Jan; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=121465

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Myotonic dystrophy: molecular windows on a complex etiology. by Korade-Mirnics Z, Babitzke P, Hoffman E. 1998 Mar 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147423

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Neuronal Nitric Oxide Synthase and Dystrophin-Deficient Muscular Dystrophy. by Chang W, Iannaccone ST, Lau KS, Masters BS, McCabe TJ, McMillan K, Padre RC, Spencer MJ, Tidball JG, Stull JT. 1996 Aug 20; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=38609


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NO skeletal muscle derived relaxing factor in Duchenne muscular dystrophy. by Bredt DS. 1998 Dec 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33925

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Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice. by Nguyen HH, Jayasinha V, Xia B, Hoyte K, Martin PT. 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122819

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Possible Influences on the Expression of X Chromosome-Linked Dystrophin Abnormalities by Heterozogosity of Autosomal Recessive Fukuyama Congenital Muscular Dystrophy. by Beggs AH, Neumann PE, Arahata K, Arikawa E, Nonaka I, Anderson MS, Kunkel LM. 1992 Jan 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=48291

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Profound misregulation of muscle-specific gene expression in facioscapulohumeral muscular dystrophy. by Tupler R, Perini G, Pellegrino MA, Green MR. 1999 Oct 26; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23032

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Social deprivation in Duchenne muscular dystrophy: population based study. by Bushby K, Raybould S, O'Donnell S, Steele JG. 2001 Nov 3; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=59456

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Structural analysis of slipped-strand DNA (S-DNA) formed in (CTG)n. (CAG)n repeats from the myotonic dystrophy locus. by Pearson CE, Wang YH, Griffith JD, Sinden RR. 1998 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=147324

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Structure and dynamics of the DNA hairpins formed by tandemly repeated CTG triplets associated with myotonic dystrophy. by Mariappan SV, Garcoa AE, Gupta G. 1996 Feb 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=145682

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The role of basal and myogenic factors in the transcriptional activation of utrophin promoter A: implications for therapeutic up-regulation in Duchenne muscular dystrophy. by Perkins KJ, Burton EA, Davies KE. 2001 Dec 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=exter nal&artid=96689

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Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes. by Hamshere MG, Newman EE, Alwazzan M, Athwal BS, Brook JD. 1997 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=23832

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Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype. by Galbiati F, Volonte D, Chu JB, Li M, Fine SW, Fu M, Bermudez J, Pedemonte M, Weidenheim KM, Pestell RG, Minetti C, Lisanti MP. 2000 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=16926

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Triple Repeat Expansion in Myotonic Dystrophy Alters the Adjacent Chromatin Structure. by Otten AD, Tapscott SJ. 1995 Jun 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41715

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Ullrich scleroatonic muscular dystrophy is caused by recessive mutations in collagen type VI. by Camacho Vanegas O, Bertini E, Zhang RZ, Petrini S, Minosse C, Sabatelli P, Giusti B, Chu ML, Pepe G. 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34700

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with muscular dystrophy, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “muscular dystrophy” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for muscular dystrophy (hyperlinks lead to article summaries): •

A case of Bartter's syndrome, gout and Becker's muscular dystrophy. Author(s): Fishel B, Zhukovsky G, Legum C, Jossiphov J, Alon M, Peer G, Iaina A, Nevo Y. Source: Clin Exp Rheumatol. 2000 May-June; 18(3): 426-7. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10895394&dopt=Abstract

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A case of limb-girdle muscular dystrophy with serum anti-nuclear antibody which led to a mistaken diagnosis of polymyositis. Author(s): Funauchi M, Nozaki Y, Yoo BS, Kinoshita K, Kanamaru A. Source: Clin Exp Rheumatol. 2002 September-October; 20(5): 707-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12412206&dopt=Abstract

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A case of merosin-negative congenital muscular dystrophy with extensive white matter abnormalities and electroencephalographic changes in a Syrian boy. Author(s): Al-Ajmi MO, Abdulla JK, Neubauer D. Source: J Med Liban. 2001 May-June; 49(3): 173-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12184464&dopt=Abstract

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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.


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A case of oculopharyngeal muscular dystrophy in a Bulgarian Jew. Author(s): Schwartz J, Rosenfeld V. Source: Journal of the American Geriatrics Society. 1993 October; 41(10): 1156-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8409167&dopt=Abstract

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A comparative gene expression analysis of Emery-Dreifuss muscular dystrophy using a cDNA microarray. Author(s): Tsukahara T, Arahata K. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 217: 253-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12491938&dopt=Abstract

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A comparison of the stress and coping strategies between the parents of children with Duchenne muscular dystrophy and children with a fever. Author(s): Chen JY, Chen SS, Jong YJ, Yang YH, Chang YY. Source: Journal of Pediatric Nursing. 2002 October; 17(5): 369-79. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12395305&dopt=Abstract

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A dystrophin-associated glycoprotein, A3a (one of 43DAG doublets), is retained in Duchenne muscular dystrophy muscle. Author(s): Yoshida M, Mizuno Y, Nonaka I, Ozawa E. Source: Journal of Biochemistry. 1993 November; 114(5): 634-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8113213&dopt=Abstract

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A missense mutation in the exon 8 of lamin A/C gene in a Japanese case of autosomal dominant limb-girdle muscular dystrophy and cardiac conduction block. Author(s): Kitaguchi T, Matsubara S, Sato M, Miyamoto K, Hirai S, Schwartz K, Bonne G. Source: Neuromuscular Disorders : Nmd. 2001 September; 11(6-7): 542-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11525883&dopt=Abstract

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A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy. Author(s): Bonifati MD, Ruzza G, Bonometto P, Berardinelli A, Gorni K, Orcesi S, Lanzi G, Angelini C. Source: Muscle & Nerve. 2000 September; 23(9): 1344-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10951436&dopt=Abstract

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A mutation in the X-linked Emery-Dreifuss muscular dystrophy gene in a patient affected with conduction cardiomyopathy. Author(s): Vohanka S, Vytopil M, Bednarik J, Lukas Z, Kadanka Z, Schildberger J, Ricotti R, Bione S, Toniolo D. Source: Neuromuscular Disorders : Nmd. 2001 May; 11(4): 411-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11369194&dopt=Abstract

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A new approach to the therapy of Duchenne muscular dystrophy with early precursors of myogenesis. Author(s): Sukhikh GT, Malaitsev VV, Bogdanova IM, Dubrovina IV, Sitnikov VF. Source: Bulletin of Experimental Biology and Medicine. 2001 December; 132(6): 1131-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12152867&dopt=Abstract

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A new dysferlin gene mutation in two Japanese families with limb-girdle muscular dystrophy 2B and Miyoshi myopathy. Author(s): Ueyama H, Kumamoto T, Nagao S, Masuda T, Horinouchi H, Fujimoto S, Tsuda T. Source: Neuromuscular Disorders : Nmd. 2001 March; 11(2): 139-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11257469&dopt=Abstract

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A new form of muscular dystrophy with mitochondrial structural abnormalities. Author(s): Ikemoto-Tsuchiya K, Nishino I, Kawai M, Morimatsu M, Nonaka I. Source: Muscle & Nerve. 2001 December; 24(12): 1710-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11745984&dopt=Abstract

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A new locus for autosomal recessive limb-girdle muscular dystrophy in a large consanguineous Tunisian family maps to chromosome 19q13.3. Author(s): Driss A, Amouri R, Ben Hamida C, Souilem S, Gouider-Khouja N, Ben Hamida M, Hentati F. Source: Neuromuscular Disorders : Nmd. 2000 June; 10(4-5): 240-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10838249&dopt=Abstract

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A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. Author(s): Wehling M, Spencer MJ, Tidball JG. Source: The Journal of Cell Biology. 2001 October 1; 155(1): 123-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11581289&dopt=Abstract

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A noninvasive means of detecting preclinical cardiomyopathy in Duchenne muscular dystrophy? Author(s): Towbin JA. Source: Journal of the American College of Cardiology. 2003 July 16; 42(2): 317-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875770&dopt=Abstract


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A novel insert mutation in gamma-sarcoglycan gene leads to severe childhood autosomal recessive muscular dystrophy. Author(s): Lin S, Ramelli GP, Moser H, Gallati S, Burgunder JM. Source: Journal of Neurology. 2002 November; 249(11): 1608-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12532930&dopt=Abstract

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A novel laminin alpha2 isoform in severe laminin alpha2 deficient congenital muscular dystrophy. Author(s): Pegoraro E, Fanin M, Trevisan CP, Angelini C, Hoffman EP. Source: Neurology. 2000 October 24; 55(8): 1128-34. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11071490&dopt=Abstract

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A novel, blood-based diagnostic assay for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Author(s): Ho M, Gallardo E, McKenna-Yasek D, De Luna N, Illa I, Brown Jr RH. Source: Annals of Neurology. 2002 January; 51(1): 129-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11782994&dopt=Abstract

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A protein truncation test for Emery-Dreifuss muscular dystrophy (EMD): detection of N-terminal truncating mutations. Author(s): de Koning Gans PA, Ginjaar I, Bakker E, Yates JR, den Dunnen JT. Source: Neuromuscular Disorders : Nmd. 1999 June; 9(4): 247-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10399752&dopt=Abstract

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A randomized comparative study of two methods for controlling Tendo Achilles contracture in Duchenne muscular dystrophy. Author(s): Hyde SA, FlLytrup I, Glent S, Kroksmark AK, Salling B, Steffensen BF, Werlauff U, Erlandsen M. Source: Neuromuscular Disorders : Nmd. 2000 June; 10(4-5): 257-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10838252&dopt=Abstract

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A sensitive assay of tumor necrosis factor alpha in sera from Duchenne muscular dystrophy patients. Author(s): Saito K, Kobayashi D, Komatsu M, Yajima T, Yagihashi A, Ishikawa Y, Minami R, Watanabe N. Source: Clinical Chemistry. 2000 October; 46(10): 1703-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11017956&dopt=Abstract

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A standardized method for the evaluation of respiratory muscle endurance in patients with Duchenne muscular dystrophy. Author(s): Matecki S, Topin N, Hayot M, Rivier F, Echenne B, Prefaut C, Ramonatxo M. Source: Neuromuscular Disorders : Nmd. 2001 March; 11(2): 171-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11257474&dopt=Abstract

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A variant of congenital muscular dystrophy. Author(s): Yoshioka M, Kuroki S, Sasaki H, Baba K, Toda T. Source: Brain & Development. 2002 January; 24(1): 24-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11751021&dopt=Abstract

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Aberrant neuronal migration in the brainstem of fukuyama-type congenital muscular dystrophy. Author(s): Saito Y, Kobayashi M, Itoh M, Saito K, Mizuguchi M, Sasaki H, Arima K, Yamamoto T, Takashima S, Sasaki M, Hayashi K, Osawa M. Source: Journal of Neuropathology and Experimental Neurology. 2003 May; 62(5): 497508. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12769189&dopt=Abstract

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Abnormal signal-averaged electrocardiogram in patients with Duchenne muscular dystrophy: comparison of time and frequency domain analyses from the signalaveraged electrocardiogram. Author(s): Kubo M, Matsuoka S, Hayabuchi Y, Akita H, Matsuka Y, Kuroda Y. Source: Clin Cardiol. 1993 October; 16(10): 723-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8222385&dopt=Abstract

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Abnormality of the myocardial sympathetic nervous system in a patient with Becker muscular dystrophy detected with iodine-123 metaiodobenzylguanidine scintigraphy. Author(s): Kaminaga T, Matsumura K, Hatanaka H, Shimizu T. Source: Clinical Nuclear Medicine. 2001 August; 26(8): 701-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11452178&dopt=Abstract

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Absence of hearing impairment in adult onset facioscapulohumeral muscular dystrophy. Author(s): Rogers MT, Zhao F, Harper PS, Stephens D. Source: Neuromuscular Disorders : Nmd. 2002 May; 12(4): 358-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12062253&dopt=Abstract

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Activities of daily living and quality of life in persons with muscular dystrophy. Author(s): Natterlund B, Ahlstrom G. Source: Journal of Rehabilitation Medicine : Official Journal of the Uems European Board of Physical and Rehabilitation Medicine. 2001 September; 33(5): 206-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11585151&dopt=Abstract


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Acute heart failure during spinal surgery in a boy with Duchenne muscular dystrophy. Author(s): Schmidt GN, Burmeister MA, Lilje C, Wappler F, Bischoff P. Source: British Journal of Anaesthesia. 2003 June; 90(6): 800-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12765898&dopt=Abstract

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Adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model. Author(s): Wang B, Li J, Xiao X. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 December 5; 97(25): 13714-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11095710&dopt=Abstract

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Adequate tidal volume with row-a-boat phenomenon in advanced Duchenne muscular dystrophy. Author(s): Yasuma F, Kato T, Naya M. Source: Chest. 2002 May; 121(5): 1726. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12006480&dopt=Abstract

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Adhalin deficiency: an unusual cause of muscular dystrophy. Author(s): Dua T, Kalra V, Sharma MC, Kabra M. Source: Indian J Pediatr. 2001 November; 68(11): 1083-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11770249&dopt=Abstract

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Affection of mimic muscles, simulating damage of the facial nerve in patients with facioscapulohumeral muscular dystrophy. Author(s): Kazakov VM. Source: European Archives of Oto-Rhino-Laryngology : Official Journal of the European Federation of Oto-Rhino-Laryngological Societies (Eufos) : Affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 1994 December; : S96-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10774323&dopt=Abstract

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Age and origin of the FCMD 3'-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population. Author(s): Colombo R, Bignamini AA, Carobene A, Sasaki J, Tachikawa M, Kobayashi K, Toda T. Source: Human Genetics. 2000 December; 107(6): 559-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11153909&dopt=Abstract

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Airway nitric oxide in Duchenne muscular dystrophy. Author(s): Straub V, Ratjen F, Amthor H, Voit T, Grasemann H. Source: The Journal of Pediatrics. 2002 July; 141(1): 132-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12091865&dopt=Abstract

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Alpha-sarcoglycanopathy previously misdiagnosed as Duchenne muscular dystrophy: implications for current diagnostics and patient care. Author(s): Schara U, Gencik M, Mortier J, Langen M, Gencikova A, Epplen JT, Mortier W. Source: European Journal of Pediatrics. 2001 July; 160(7): 452-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11475588&dopt=Abstract

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Alterations of the retino-cortical conduction in patients affected by classical congenital muscular dystrophy (CI-CMD) with merosin deficiency. Author(s): Tormene AP, Trevisan C, Martinello F, Riva C, Pastorello E. Source: Documenta Ophthalmologica. Advances in Ophthalmology. 1999; 98(2): 127-38. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10946999&dopt=Abstract

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Altered regional brain glucose metabolism in Duchenne muscular dystrophy: a pet study. Author(s): Lee JS, Pfund Z, Juhasz C, Behen ME, Muzik O, Chugani DC, Nigro MA, Chugani HT. Source: Muscle & Nerve. 2002 October; 26(4): 506-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12362416&dopt=Abstract

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Aminoglycoside treatment for muscular dystrophy is scientifically rational, but is it clinically effective? Author(s): Hirano M. Source: Curr Neurol Neurosci Rep. 2002 January; 2(1): 53-4. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11898583&dopt=Abstract

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An attempt of gene therapy in Duchenne muscular dystrophy: overexpression of utrophin in transgenic mdx mice. Author(s): Gillis JM. Source: Acta Neurol Belg. 2000 September; 100(3): 146-50. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11098286&dopt=Abstract

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An autosomal dominant early adult-onset distal muscular dystrophy. Author(s): Zimprich F, Djamshidian A, Hainfellner JA, Budka H, Zeitlhofer J. Source: Muscle & Nerve. 2000 December; 23(12): 1876-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11102913&dopt=Abstract


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An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22. Author(s): Muntoni F, Taylor J, Sewry CA, Naom I, Dubowitz V. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. 1998; 2(1): 19-26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10726842&dopt=Abstract

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An inherited 4q35-EcoRI-DNA-fragment of 35 kb in a family with a sporadic case of facioscapulohumeral muscular dystrophy (FSHD). Author(s): Busse K, Kohler J, Stegmann K, Pongratz D, Koch MC, Schreiber H. Source: Neuromuscular Disorders : Nmd. 2000 March; 10(3): 178-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10734264&dopt=Abstract

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An STS map of the limb girdle muscular dystrophy type 2A region. Author(s): Richard I, Roudaut C, Fougerousse F, Chiannilkulchai N, Beckmann JS. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. 1995 October; 6(10): 754-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8563179&dopt=Abstract

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Anaesthetic management of a patient with Emery-Dreifuss muscular dystrophy. Author(s): Shende D, Agarwal R. Source: Anaesthesia and Intensive Care. 2002 June; 30(3): 372-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12075650&dopt=Abstract

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Analysis of dinucleotide repeat loci of dystrophin gene for carrier detection, germline mosaicism and de novo mutations in Duchenne muscular dystrophy. Author(s): Chaturvedi LS, Mittal RD, Srivastava S, Mukherjee M, Mittal B. Source: Clinical Genetics. 2000 September; 58(3): 234-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11076047&dopt=Abstract

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Analysis of dystrophin mRNA from skeletal muscle but not from lymphocytes led to identification of a novel nonsense mutation in a carrier of Duchenne muscular dystrophy. Author(s): Ito T, Takeshima Y, Yagi M, Kamei S, Wada H, Nakamura H, Matsuo M. Source: Journal of Neurology. 2003 May; 250(5): 581-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12736738&dopt=Abstract

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Andre Barbeau and the oculopharyngeal muscular dystrophy in French Canada and North America. Author(s): Bouchard JP. Source: Neuromuscular Disorders : Nmd. 1997 October; 7 Suppl 1: S5-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9392008&dopt=Abstract

Studies 117

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Animal models for muscular dystrophy show different patterns of sarcolemmal disruption. Author(s): Straub V, Rafael JA, Chamberlain JS, Campbell KP. Source: The Journal of Cell Biology. 1997 October 20; 139(2): 375-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9334342&dopt=Abstract

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Animal models for muscular dystrophy: valuable tools for the development of therapies. Author(s): Allamand V, Campbell KP. Source: Human Molecular Genetics. 2000 October; 9(16): 2459-67. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11005802&dopt=Abstract

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Apnoea in Duchenne muscular dystrophy. Author(s): Barbe F, Quera-Salva MA, Agusti AG. Source: Thorax. 1995 October; 50(10): 1123. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7491569&dopt=Abstract

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Assessment of cardiac function in adolescents with Duchenne muscular dystrophy: importance of neurohormones. Author(s): Ramaciotti C, Scott WA, Lemler MS, Haverland C, Iannaccone ST. Source: Journal of Child Neurology. 2002 March; 17(3): 191-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12026234&dopt=Abstract

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Assessment of left ventricular systolic and diastolic functions in children with merosin-positive congenital muscular dystrophy. Author(s): Ceviz N, Alehan F, Alehan D, Ozme S, Akcoren Z, Kale G, Topaloglu H. Source: International Journal of Cardiology. 2003 February; 87(2-3): 129-33; Discussion 133-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12559529&dopt=Abstract

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Assignment of a form of congenital muscular dystrophy with secondary merosin deficiency to chromosome 1q42. Author(s): Brockington M, Sewry CA, Herrmann R, Naom I, Dearlove A, Rhodes M, Topaloglu H, Dubowitz V, Voit T, Muntoni F. Source: American Journal of Human Genetics. 2000 February; 66(2): 428-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10677302&dopt=Abstract

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Asymptomatic Becker muscular dystrophy: histological changes in biopsied muscles. Author(s): Tachi N, Watanabe Y, Ohya K, Chiba S. Source: Acta Paediatr Jpn. 1993 October; 35(5): 409-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8256625&dopt=Abstract


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Ataxia and congenital muscular dystrophy: the follow-up of a new specific phenotype. Author(s): Trevisan CP, Pastorello E, Tonello S, Armani M, Rigoni MT, Tormene AP, Freda MP, Zortea M, Lombardi S. Source: Brain & Development. 2001 March; 23(2): 108-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11248459&dopt=Abstract

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Augmented synthesis and differential localization of heparan sulfate proteoglycans in Duchenne muscular dystrophy. Author(s): Alvarez K, Fadic R, Brandan E. Source: Journal of Cellular Biochemistry. 2002; 85(4): 703-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11968010&dopt=Abstract

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Autosomal dominant Emery-Dreifuss muscular dystrophy: a new family with late diagnosis. Author(s): Colomer J, Iturriaga C, Bonne G, Schwartz K, Manilal S, Morris GE, Puche M, Fernandez-Alvarez E. Source: Neuromuscular Disorders : Nmd. 2002 January; 12(1): 19-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11731280&dopt=Abstract

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Autosomal dominant limb-girdle muscular dystrophy: a large kindred with evidence for anticipation. Author(s): Gamez J, Navarro C, Andreu AL, Fernandez JM, Palenzuela L, Tejeira S, Fernandez-Hojas R, Schwartz S, Karadimas C, DiMauro S, Hirano M, Cervera C. Source: Neurology. 2001 February 27; 56(4): 450-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11222786&dopt=Abstract

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Basement membrane abnormality in merosin-negative congenital muscular dystrophy. Author(s): Osari S, Kobayashi O, Yamashita Y, Matsuishi T, Goto M, Tanabe Y, Migita T, Nonaka I. Source: Acta Neuropathologica. 1996; 91(4): 332-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8928608&dopt=Abstract

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Basic fibroblast growth factor and muscular dystrophy. Author(s): Lefaucheur JP, Sebille A. Source: Annals of Neurology. 1994 November; 36(5): 800. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7979228&dopt=Abstract

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Basic fibroblast growth factor promotes in vivo muscle regeneration in murine muscular dystrophy. Author(s): Lefaucheur JP, Sebille A. Source: Neuroscience Letters. 1995 December 29; 202(1-2): 121-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8787846&dopt=Abstract

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Becker muscular dystrophy associated with focal myositis on bone scintigraphy. Author(s): Minshew PT, Silverman ED, Samuels-Botts C. Source: Clinical Nuclear Medicine. 2000 December; 25(12): 1010-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11129135&dopt=Abstract

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Becker muscular dystrophy combined with X-linked Charcot-Marie-Tooth neuropathy. Author(s): Bergmann C, Senderek J, Hermanns B, Jauch A, Janssen B, Schroder JM, Karch D. Source: Muscle & Nerve. 2000 May; 23(5): 818-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10797409&dopt=Abstract

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Becker muscular dystrophy presenting as eosinophilic inflammatory myopathy in an infant. Author(s): Weinstock A, Green C, Cohen BH, Prayson RA. Source: Journal of Child Neurology. 1997 February; 12(2): 146-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9075026&dopt=Abstract

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Becker muscular dystrophy presenting with complete heart block in the sixth decade. Author(s): Quinlivan R, Ball J, Dunckley M, Thomas DJ, Flinter F, Morgan-Hughes J. Source: Journal of Neurology. 1995 June; 242(6): 398-400. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7561969&dopt=Abstract

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Becker muscular dystrophy with bundle branch reentry ventricular tachycardia. Author(s): Negri SM, Cowan MD. Source: Journal of Cardiovascular Electrophysiology. 1998 June; 9(6): 652-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9654233&dopt=Abstract

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Becker muscular dystrophy with onset after 60 years. Author(s): Heald A, Anderson LV, Bushby KM, Shaw PJ. Source: Neurology. 1994 December; 44(12): 2388-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7991131&dopt=Abstract


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Becker muscular dystrophy: an unusual presentation. Author(s): Bush A, Dubowitz V. Source: Archives of Disease in Childhood. 1994 January; 70(1): 71. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8110014&dopt=Abstract

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Becker muscular dystrophy-related cardiomyopathy: a favorable response to medical therapy. Author(s): Doing AH, Renlund DG, Smith RA. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2002 April; 21(4): 496-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11927228&dopt=Abstract

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Becker-like muscular dystrophy in sisters. Author(s): Dioszeghy P, Molnar M, Mechler F. Source: European Archives of Psychiatry and Clinical Neuroscience. 1995; 245(6): 326-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8527470&dopt=Abstract

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Becker's muscular dystrophy: a case report. Author(s): Seid D. Source: Ethiop Med J. 1997 January; 35(1): 63-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9293149&dopt=Abstract

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Becker-type muscular dystrophy associated with hypertrophic cardiomyopathy. Author(s): Hayashi Y, Ikeda U, Ogawa T, Miyashita H, Sekiguchi H, Arahata K, Shimada K. Source: American Heart Journal. 1994 December; 128(6 Pt 1): 1264-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7985617&dopt=Abstract

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Beta-sarcoglycan (A3b) mutations cause autosomal recessive muscular dystrophy with loss of the sarcoglycan complex. Author(s): Bonnemann CG, Modi R, Noguchi S, Mizuno Y, Yoshida M, Gussoni E, McNally EM, Duggan DJ, Angelini C, Hoffman EP. Source: Nature Genetics. 1995 November; 11(3): 266-73. Erratum In: Nat Genet 1996 January; 12(1): 110. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7581449&dopt=Abstract

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Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12. Author(s): Lim LE, Duclos F, Broux O, Bourg N, Sunada Y, Allamand V, Meyer J, Richard I, Moomaw C, Slaughter C, et al. Source: Nature Genetics. 1995 November; 11(3): 257-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7581448&dopt=Abstract

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Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 23-24 November 2001, Naarden, The Netherlands. Author(s): Pepe G, Bertini E, Bonaldo P, Bushby K, Giusti B, de Visser M, Guicheney P, Lattanzi G, Merlini L, Muntoni F, Nishino I, Nonaka I, Yaou RB, Sabatelli P, Sewry C, Topaloglu H, van der Kooi A. Source: Neuromuscular Disorders : Nmd. 2002 December; 12(10): 984-93. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467756&dopt=Abstract

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Bethlem myopathy is not allelic to limb-girdle muscular dystrophy type 1A. Author(s): Speer MC, Yamaoka LH, Stajich J, Lewis K, Pericak-Vance MA, Stacy R, Tandan R, Fries TJ. Source: American Journal of Medical Genetics. 1995 August 28; 58(2): 197-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8533815&dopt=Abstract

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Bethlem myopathy: a slowly progressive congenital muscular dystrophy with contractures. Author(s): Jobsis GJ, Boers JM, Barth PG, de Visser M. Source: Brain; a Journal of Neurology. 1999 April; 122 ( Pt 4): 649-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10219778&dopt=Abstract

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Bladder dysfunction in Duchenne muscular dystrophy. Author(s): MacLeod M, Kelly R, Robb SA, Borzyskowski M. Source: Archives of Disease in Childhood. 2003 April; 88(4): 347-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12651768&dopt=Abstract

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Blood loss in Duchenne muscular dystrophy: vascular smooth muscle dysfunction? Author(s): Noordeen MH, Haddad FS, Muntoni F, Gobbi P, Hollyer JS, Bentley G. Source: Journal of Pediatric Orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America. 1999 July; 8(3): 212-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10399127&dopt=Abstract

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Body composition and energy expenditure in Duchenne muscular dystrophy. Author(s): Zanardi MC, Tagliabue A, Orcesi S, Berardinelli A, Uggetti C, Pichiecchio A. Source: European Journal of Clinical Nutrition. 2003 February; 57(2): 273-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12571659&dopt=Abstract

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Body composition determined with MR in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and normal subjects. Author(s): Leroy-Willig A, Willig TN, Henry-Feugeas MC, Frouin V, Marinier E, Boulier A, Barzic F, Schouman-Claeys E, Syrota A. Source: Magnetic Resonance Imaging. 1997; 15(7): 737-44. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9309604&dopt=Abstract


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Bone mineral density and fractures in boys with Duchenne muscular dystrophy. Author(s): Larson CM, Henderson RC. Source: Journal of Pediatric Orthopedics. 2000 January-February; 20(1): 71-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10641693&dopt=Abstract

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Botulinum toxin for amelioration of knee contracture in Duchenne muscular dystrophy. Author(s): von Wendt LO, Autti-Ramo IS. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. 1999; 3(4): 175-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10476367&dopt=Abstract

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Brain abnormalities in Duchenne muscular dystrophy: phosphorus-31 magnetic resonance spectroscopy and neuropsychological study. Author(s): Tracey I, Scott RB, Thompson CH, Dunn JF, Barnes PR, Styles P, Kemp GJ, Rae CD, Pike M, Radda GK. Source: Lancet. 1995 May 20; 345(8960): 1260-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7746055&dopt=Abstract

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Brain alterations in the classical form of congenital muscular dystrophy. Clinical and neuroimaging follow-up of 12 cases and correlation with the expression of merosin in muscle. Author(s): Trevisan CP, Martinello F, Ferruzza E, Fanin M, Chevallay M, Tome FM. Source: Child's Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery. 1996 October; 12(10): 604-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8934020&dopt=Abstract

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Brain biochemistry in Duchenne muscular dystrophy: a 1H magnetic resonance and neuropsychological study. Author(s): Rae C, Scott RB, Thompson CH, Dixon RM, Dumughn I, Kemp GJ, Male A, Pike M, Styles P, Radda GK. Source: Journal of the Neurological Sciences. 1998 October 8; 160(2): 148-57. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9849797&dopt=Abstract

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Brain function in Duchenne muscular dystrophy. Author(s): Anderson JL, Head SI, Rae C, Morley JW. Source: Brain; a Journal of Neurology. 2002 January; 125(Pt 1): 4-13. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11834588&dopt=Abstract

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Brain magnetic resonance imaging abnormalities in merosin-positive congenital muscular dystrophy. Author(s): Philpot J, Pennock J, Cowan F, Sewry CA, Dubowitz V, Bydder G, Muntoni F. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. 2000; 4(3): 109-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10872105&dopt=Abstract

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Brain MR in Fukuyama congenital muscular dystrophy. Author(s): Aida N, Tamagawa K, Takada K, Yagishita A, Kobayashi N, Chikumaru K, Iwamoto H. Source: Ajnr. American Journal of Neuroradiology. 1996 April; 17(4): 605-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8730178&dopt=Abstract

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Breached cerebral glia limitans-basal lamina complex in Fukuyama-type congenital muscular dystrophy. Author(s): Saito Y, Murayama S, Kawai M, Nakano I. Source: Acta Neuropathologica. 1999 October; 98(4): 330-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10502035&dopt=Abstract

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Brief report: deficiency of a dystrophin-associated glycoprotein (adhalin) in a patient with muscular dystrophy and cardiomyopathy. Author(s): Fadic R, Sunada Y, Waclawik AJ, Buck S, Lewandoski PJ, Campbell KP, Lotz BP. Source: The New England Journal of Medicine. 1996 February 8; 334(6): 362-6. Erratum In: N Engl J Med 1996 March 28; 334(13): 871. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8538707&dopt=Abstract

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Broader clinical spectrum of Fukuyama-type congenital muscular dystrophy manifested by haplotype analysis. Author(s): Yoshioka M, Toda T, Kuroki S, Hamano K. Source: Journal of Child Neurology. 1999 November; 14(11): 711-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10593547&dopt=Abstract

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Building the French Muscular Dystrophy Association: the role of doctor/patient interactions. Author(s): Bach MA. Source: Social History of Medicine : the Journal of the Society for the Social History of Medicine / Sshm. 1998 August; 11(2): 233-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11620429&dopt=Abstract


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Calcium currents and transients in co-cultured contracting normal and Duchenne muscular dystrophy human myotubes. Author(s): Imbert N, Vandebrouck C, Duport G, Raymond G, Hassoni AA, Constantin B, Cullen MJ, Cognard C. Source: The Journal of Physiology. 2001 July 15; 534(Pt. 2): 343-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11454955&dopt=Abstract

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Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy. Author(s): Chae J, Minami N, Jin Y, Nakagawa M, Murayama K, Igarashi F, Nonaka I. Source: Neuromuscular Disorders : Nmd. 2001 September; 11(6-7): 547-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11525884&dopt=Abstract

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Cardiac arrest during major spinal scoliosis surgery in a patient with Duchenne's muscular dystrophy undergoing intravenous anaesthesia. Author(s): Irwin MG, Henderson M. Source: Anaesthesia and Intensive Care. 1995 October; 23(5): 626-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8787270&dopt=Abstract

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Cardiac involvement in myotonic dystrophy, Becker muscular dystrophy and mitochondrial myopathy: a five-year follow-up. Author(s): Finsterer J, Stollberger C, Blazek G, Spahits E. Source: The Canadian Journal of Cardiology. 2001 October; 17(10): 1061-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11694896&dopt=Abstract

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Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy. Author(s): Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda S, Sato K, Mori S, Ito H, Moriyama M. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 2003 May; 83(5): 711-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12746480&dopt=Abstract

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Cardiomyopathy and atrioventricular block in Emery-Dreifuss muscular dystrophy--a case report. Author(s): Kanada M, Demirtas M, Guzel R, San M, Tuncer I. Source: Angiology. 2002 January-February; 53(1): 109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11863303&dopt=Abstract

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Cardiomyopathy in a carrier of Duchenne's muscular dystrophy. Author(s): Davies JE, Winokur TS, Aaron MF, Benza RL, Foley BA, Holman WL. Source: The Journal of Heart and Lung Transplantation : the Official Publication of the International Society for Heart Transplantation. 2001 July; 20(7): 781-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11448811&dopt=Abstract

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Cardiomyopathy in animal models of muscular dystrophy. Author(s): Heydemann A, Wheeler MT, McNally EM. Source: Current Opinion in Cardiology. 2001 May; 16(3): 211-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11357018&dopt=Abstract

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Cardiomyopathy may be the only clinical manifestation in female carriers of Duchenne muscular dystrophy. Author(s): Mirabella M, Servidei S, Manfredi G, Ricci E, Frustaci A, Bertini E, Rana M, Tonali P. Source: Neurology. 1993 November; 43(11): 2342-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8232953&dopt=Abstract

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Cardiovascular autonomic control in Becker muscular dystrophy. Author(s): Vita G, Di Leo R, De Gregorio C, Papalia A, Rodolico C, Coglitore S, Messina C. Source: Journal of the Neurological Sciences. 2001 May 1; 186(1-2): 45-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11412871&dopt=Abstract

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Carrier detection and prenatal diagnosis in Duchenne/Becker muscular dystrophy. Author(s): Panigrahi I, Mittal B. Source: Indian Pediatrics. 2001 June; 38(6): 631-9. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11418728&dopt=Abstract

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Carrier detection and prenatal molecular diagnosis in a Duchenne muscular dystrophy family without any affected relative available. Author(s): Alcantara MA, Garcia-Cavazos R, Hernandez-U E, Gonzalez-del Angel A, Carnevale A, Orozco L. Source: Annales De Genetique. 2001 July-September; 44(3): 149-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11694228&dopt=Abstract

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Carrier detection in non-deletional Duchenne/Becker muscular dystrophy families using polymorphic dinucleotide (CA) repeat loci of dystrophin gene. Author(s): Chaturvedi LS, Srivastava S, Mukherjee M, Mittal RD, Phadke SR, Pradhan S, Mittal B. Source: The Indian Journal of Medical Research. 2001 January; 113: 19-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11280167&dopt=Abstract


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Carrier detection of Duchenne/Becker muscular dystrophy by using fluorescent linkage analysis in Taiwan. Author(s): Lee CC, Wu MC, Wu JY, Li TC, Tsai FJ, Tsai CH. Source: Acta Paediatr Taiwan. 2000 March-April; 41(2): 69-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10927942&dopt=Abstract

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Caspase 3 expression correlates with skeletal muscle apoptosis in Duchenne and facioscapulo human muscular dystrophy. A potential target for pharmacological treatment? Author(s): Sandri M, El Meslemani AH, Sandri C, Schjerling P, Vissing K, Andersen JL, Rossini K, Carraro U, Angelini C. Source: Journal of Neuropathology and Experimental Neurology. 2001 March; 60(3): 302-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11245214&dopt=Abstract

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Cause of progression in Duchenne muscular dystrophy: impaired differentiation more probable than replicative aging. Author(s): Oexle K, Kohlschutter A. Source: Neuropediatrics. 2001 June; 32(3): 123-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11521207&dopt=Abstract

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Caveolae and caveolin-3 in muscular dystrophy. Author(s): Galbiati F, Razani B, Lisanti MP. Source: Trends in Molecular Medicine. 2001 October; 7(10): 435-41. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11597517&dopt=Abstract

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Caveolin proteins in signaling, oncogenic transformation and muscular dystrophy. Author(s): Razani B, Schlegel A, Lisanti MP. Source: Journal of Cell Science. 2000 June; 113 ( Pt 12): 2103-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10825283&dopt=Abstract

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CDNA microarray analysis of gene expression in fibroblasts of patients with X-linked Emery-Dreifuss muscular dystrophy. Author(s): Tsukahara T, Tsujino S, Arahata K. Source: Muscle & Nerve. 2002 June; 25(6): 898-901. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12115980&dopt=Abstract

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Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy. Author(s): Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Source: American Journal of Respiratory and Critical Care Medicine. 2001 December 15; 164(12): 2191-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11751186&dopt=Abstract

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Changes of laminin beta 2 chain expression in congenital muscular dystrophy. Author(s): Cohn RD, Herrmann R, Wewer UM, Voit T. Source: Neuromuscular Disorders : Nmd. 1997 September; 7(6-7): 373-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9327401&dopt=Abstract

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Charles Bell (1774-1842) and an early case of muscular dystrophy. The Third Meryon Society Lecture read at Worcester College, Oxford on 28 July, 2000. Author(s): Gardner-Thorpe C. Source: Neuromuscular Disorders : Nmd. 2002 March; 12(3): 318-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11801406&dopt=Abstract

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Circadian rhythm and variability of heart rate in Duchenne-type progressive muscular dystrophy. Author(s): Yotsukura M, Sasaki K, Kachi E, Sasaki A, Ishihara T, Ishikawa K. Source: The American Journal of Cardiology. 1995 November 1; 76(12): 947-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7484837&dopt=Abstract

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Clinical and experimental results on cardiac troponin expression in Duchenne muscular dystrophy. Author(s): Hammerer-Lercher A, Erlacher P, Bittner R, Korinthenberg R, Skladal D, Sorichter S, Sperl W, Puschendorf B, Mair J. Source: Clinical Chemistry. 2001 March; 47(3): 451-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11238296&dopt=Abstract

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Clinical and histopathological study of merosin-deficient and merosin-positive congenital muscular dystrophy. Author(s): Talim B, Kale G, Topaloglu H, Akcoren Z, Caglar M, Gogus S, Elkay M. Source: Pediatric and Developmental Pathology : the Official Journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2000 March-April; 3(2): 168-76. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10679036&dopt=Abstract

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Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1). Author(s): Mercuri E, Talim B, Moghadaszadeh B, Petit N, Brockington M, Counsell S, Guicheney P, Muntoni F, Merlini L. Source: Neuromuscular Disorders : Nmd. 2002 October; 12(7-8): 631-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12207930&dopt=Abstract


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Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene. Author(s): Bonne G, Mercuri E, Muchir A, Urtizberea A, Becane HM, Recan D, Merlini L, Wehnert M, Boor R, Reuner U, Vorgerd M, Wicklein EM, Eymard B, Duboc D, Penisson-Besnier I, Cuisset JM, Ferrer X, Desguerre I, Lacombe D, Bushby K, Pollitt C, Toniolo D, Fardeau M, Schwartz K, Muntoni F. Source: Annals of Neurology. 2000 August; 48(2): 170-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10939567&dopt=Abstract

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Clinical and molecular studies in a unique family with autosomal dominant limbgirdle muscular dystrophy and Paget disease of bone. Author(s): Kimonis VE, Kovach MJ, Waggoner B, Leal S, Salam A, Rimer L, Davis K, Khardori R, Gelber D. Source: Genetics in Medicine : Official Journal of the American College of Medical Genetics. 2000 July-August; 2(4): 232-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11252708&dopt=Abstract

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Clinical and molecular study in congenital muscular dystrophy with partial laminin alpha 2 (LAMA2) deficiency. Author(s): Tezak Z, Prandini P, Boscaro M, Marin A, Devaney J, Marino M, Fanin M, Trevisan CP, Park J, Tyson W, Finkel R, Garcia C, Angelini C, Hoffman EP, Pegoraro E. Source: Human Mutation. 2003 February; 21(2): 103-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12552556&dopt=Abstract

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Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in Emery-Dreifuss muscular dystrophy: a long-term longitudinal study. Author(s): Boriani G, Gallina M, Merlini L, Bonne G, Toniolo D, Amati S, Biffi M, Martignani C, Frabetti L, Bonvicini M, Rapezzi C, Branzi A. Source: Stroke; a Journal of Cerebral Circulation. 2003 April; 34(4): 901-8. Epub 2003 March 20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12649505&dopt=Abstract

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Clinical results of early orthopaedic management in Duchenne muscular dystrophy. Author(s): Goertzen M, Baltzer A, Voit T. Source: Neuropediatrics. 1995 October; 26(5): 257-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8552216&dopt=Abstract

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Clinical significance of late potential in patients with Duchenne muscular dystrophy. Author(s): Kubo M, Matsuoka S, Taguchi Y, Akita H, Kuroda Y. Source: Pediatric Cardiology. 1993 October; 14(4): 214-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8255794&dopt=Abstract

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Clinical variability and molecular diagnosis in a four-generation family with Xlinked Emery-Dreifuss muscular dystrophy. Author(s): Canki-Klain N, Recan D, Milicic D, Llense S, Leturcq F, Deburgrave N, Kaplan JC, Debevec M, Zurak N. Source: Croatian Medical Journal. 2000 December; 41(4): 389-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11063761&dopt=Abstract

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Clinicopathological study on eyes from cases of Fukuyama type congenital muscular dystrophy. Author(s): Hino N, Kobayashi M, Shibata N, Yamamoto T, Saito K, Osawa M. Source: Brain & Development. 2001 March; 23(2): 97-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11248458&dopt=Abstract

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Coagulation and fibrinolysis disorder in muscular dystrophy. Author(s): Saito T, Takenaka M, Miyai I, Yamamoto Y, Matsumura T, Nozaki S, Kang J. Source: Muscle & Nerve. 2001 March; 24(3): 399-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11353426&dopt=Abstract

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Coats' disease and Duchenne muscular dystrophy. Author(s): Bobart A, Brosnahan D. Source: Eye (London, England). 2001 August; 15(Pt 4): 563-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11767047&dopt=Abstract

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Collaborative translational research leading to multicenter clinical trials in Duchenne muscular dystrophy: the Cooperative International Neuromuscular Research Group (CINRG). Author(s): Escolar DM, Henricson EK, Pasquali L, Gorni K, Hoffman EP. Source: Neuromuscular Disorders : Nmd. 2002 October; 12 Suppl 1: S147-154. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12206809&dopt=Abstract

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Collagen type VI and related disorders: Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Author(s): Bertini E, Pepe G. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. 2002; 6(4): 193-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12374585&dopt=Abstract

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Comparative analysis of PCR-deletion detection and immunohistochemistry in Brazilian Duchenne and Becker muscular dystrophy patients. Author(s): Werneck LC, Scola RH, Maegawa GH, Werneck MC. Source: American Journal of Medical Genetics. 2001 October 1; 103(2): 115-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11568916&dopt=Abstract


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Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis. Author(s): Lemmers RJL, de Kievit P, van Geel M, van der Wielen MJ, Bakker E, Padberg GW, Frants RR, van der Maarel SM. Source: Annals of Neurology. 2001 December; 50(6): 816-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11761483&dopt=Abstract

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Complete skipping of exon 66 due to novel mutations of the dystrophin gene was identified in two Japanese families of Duchenne muscular dystrophy with severe mental retardation. Author(s): Wibawa T, Takeshima Y, Mitsuyoshi I, Wada H, Surono A, Nakamura H, Matsuo M. Source: Brain & Development. 2000 March; 22(2): 107-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10722962&dopt=Abstract

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Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13 in American families suggests the existence of a second causal mutation. Author(s): Stajich JM, Gilchrist JM, Lennon F, Lee A, Yamaoka L, Rosi B, Gaskell PC, Pritchard M, Donald L, Roses AD, Vance JM, Pericak-Vance MA. Source: Neuromuscular Disorders : Nmd. 1997 October; 7 Suppl 1: S75-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9392021&dopt=Abstract

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Confocal analysis of the dystrophin protein complex in muscular dystrophy. Author(s): Draviam R, Billington L, Senchak A, Hoffman EP, Watkins SC. Source: Muscle & Nerve. 2001 February; 24(2): 262-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11180210&dopt=Abstract

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Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome. Author(s): Villanova M, Mercuri E, Bertini E, Sabatelli P, Morandi L, Mora M, Sewry C, Brockington M, Brown SC, Ferreiro A, Maraldi NM, Toda T, Guicheney P, Merlini L, Muntoni F. Source: Neuromuscular Disorders : Nmd. 2000 December; 10(8): 541-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11053679&dopt=Abstract

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Congenital muscular dystrophy in Israeli families. Author(s): Rachmiel M, Nevo Y, Lahat E, Kutai M, Harel S, Shahar E. Source: Journal of Child Neurology. 2002 May; 17(5): 333-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12150578&dopt=Abstract

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Congenital muscular dystrophy with adducted thumbs, ptosis, external ophthalmoplegia, mental retardation and cerebellar hypoplasia: a novel form of CMD. Author(s): Voit T, Parano E, Straub V, Schroder JM, Schaper J, Pavone P, Falsaperla R, Pavone L, Herrmann R. Source: Neuromuscular Disorders : Nmd. 2002 October; 12(7-8): 623-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12207929&dopt=Abstract

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Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient. Author(s): Belpaire-Dethiou MC, Saito K, Fukuyama Y, Kondo-Iida E, Toda T, Duprez T, Verellen-Dumoulin C, Van den Bergh PY. Source: Neuromuscular Disorders : Nmd. 1999 June; 9(4): 251-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10399753&dopt=Abstract

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Congenital muscular dystrophy with partial deficiency of merosin. Author(s): Tachi N, Kamimura S, Ohya K, Chiba S, Sasaki K. Source: Journal of the Neurological Sciences. 1997 October 3; 151(1): 25-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9335006&dopt=Abstract

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Congenital muscular dystrophy with primary partial laminin alpha2 chain deficiency: molecular study. Author(s): He Y, Jones KJ, Vignier N, Morgan G, Chevallay M, Barois A, EstournetMathiaud B, Hori H, Mizuta T, Tome FM, North KN, Guicheney P. Source: Neurology. 2001 October 9; 57(7): 1319-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11591858&dopt=Abstract

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Congenital muscular dystrophy with secondary merosin deficiency and normal brain MRI: a novel entity? Author(s): Mercuri E, Sewry CA, Brown SC, Brockington M, Jungbluth H, DeVile C, Counsell S, Manzur A, Muntoni F. Source: Neuropediatrics. 2000 August; 31(4): 186-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11071142&dopt=Abstract

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Congenital muscular dystrophy. Author(s): Huang FL, Mak SC, Chi CS. Source: Zhonghua Yi Xue Za Zhi (Taipei). 2000 February; 63(2): 165-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10677931&dopt=Abstract

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Congenital muscular dystrophy: searching for a definition after 98 years. Author(s): Mendell JR. Source: Neurology. 2001 April 24; 56(8): 993-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11320168&dopt=Abstract


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Contrasting evolutionary histories of two introns of the duchenne muscular dystrophy gene, Dmd, in humans. Author(s): Nachman MW, Crowell SL. Source: Genetics. 2000 August; 155(4): 1855-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10924480&dopt=Abstract

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Controversial muscular dystrophy therapy goes to court. Author(s): Birmingham K. Source: Nature Medicine. 1997 October; 3(10): 1058. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9334704&dopt=Abstract

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Correction of blepharoptosis in oculopharyngeal muscular dystrophy. Author(s): Kang DH, Koo SH, Ahn DS, Park SH, Yoon ES. Source: Annals of Plastic Surgery. 2002 October; 49(4): 419-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12370650&dopt=Abstract

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Correlation between progression of spinal deformity and pulmonary function in Duchenne muscular dystrophy. Author(s): Yamashita T, Kanaya K, Yokogushi K, Ishikawa Y, Minami R. Source: Journal of Pediatric Orthopedics. 2001 January-February; 21(1): 113-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11176364&dopt=Abstract

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Correlation of clinical function and muscle CT scan images in limb-girdle muscular dystrophy. Author(s): Vlak M, van der Kooi E, Angelini C. Source: Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2000; 21(5 Suppl): S975-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11382199&dopt=Abstract

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Correlation of laboratory and clinical findings with the location of Xp21 deletion in Duchenne muscular dystrophy. Author(s): Tasdemir HA, Topaloglu H, Dincer P, Gogus S, Kotiloglu E, Ozdirim E, Yalaz K. Source: Turk J Pediatr. 1997 July-September; 39(3): 317-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9339110&dopt=Abstract

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Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Author(s): Hukins CA, Hillman DR. Source: American Journal of Respiratory and Critical Care Medicine. 2000 January; 161(1): 166-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10619815&dopt=Abstract

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De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sexdependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Author(s): van der Maarel SM, Deidda G, Lemmers RJ, van Overveld PG, van der Wielen M, Hewitt JE, Sandkuijl L, Bakker B, van Ommen GJ, Padberg GW, Frants RR. Source: American Journal of Human Genetics. 2000 January; 66(1): 26-35. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10631134&dopt=Abstract

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Decreased bone density in ambulatory patients with duchenne muscular dystrophy. Author(s): Aparicio LF, Jurkovic M, DeLullo J. Source: Journal of Pediatric Orthopedics. 2002 March-April; 22(2): 179-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11856925&dopt=Abstract

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Decreased sperm function of patients with myotonic muscular dystrophy. Author(s): Hortas ML, Castilla JA, Gil MT, Molina J, Garrido ML, Morell M, Redondo M. Source: Human Reproduction (Oxford, England). 2000 February; 15(2): 445-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10655320&dopt=Abstract

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Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy. Author(s): Gache Y, Chavanas S, Lacour JP, Wiche G, Owaribe K, Meneguzzi G, Ortonne JP. Source: The Journal of Clinical Investigation. 1996 May 15; 97(10): 2289-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8636409&dopt=Abstract

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Defective glycosylation in muscular dystrophy. Author(s): Muntoni F, Brockington M, Blake DJ, Torelli S, Brown SC. Source: Lancet. 2002 November 2; 360(9343): 1419-21. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12424008&dopt=Abstract

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Defective growth in vitro of Duchenne Muscular Dystrophy myoblasts: the molecular and biochemical basis. Author(s): Melone MA, Peluso G, Petillo O, Galderisi U, Cotrufo R. Source: Journal of Cellular Biochemistry. 1999 November; 76(1): 118-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10581006&dopt=Abstract

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Deficiency of the 50 kDa dystrophin-associated-glycoprotein (adhalin) in an Indian autosomal recessive limb girdle muscular dystrophy patient : immunochemical analysis and clinical aspects. Author(s): Handa V, Mital A, Gupta M, Goyle S. Source: Neurology India. 2001 March; 49(1): 19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11303236&dopt=Abstract


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Deflazacort treatment of Duchenne muscular dystrophy. Author(s): Biggar WD, Gingras M, Fehlings DL, Harris VA, Steele CA. Source: The Journal of Pediatrics. 2001 January; 138(1): 45-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11148511&dopt=Abstract

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Delayed diagnosis of Duchenne muscular dystrophy. Author(s): Mohamed K, Appleton R, Nicolaides P. Source: European Journal of Paediatric Neurology : Ejpn : Official Journal of the European Paediatric Neurology Society. 2000; 4(5): 219-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11030068&dopt=Abstract

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Deletion screening and carrier detection in Duchenne muscular dystrophy in Polish population via direct analysis of DNA and RNA transcripts. Author(s): Kwiatkowska J, Lisiecka D, Sowinska J, Marszal E, Emich-Widera E, Ciesielski T, Szczegola-Przymusiak A, Nuc P, Chlebowska H, Zimowski J, GalasZgorzalewicz B, Slomski R. Source: Biochimie. 1997 July; 79(7): 439-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9352094&dopt=Abstract

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Denaturing gradient gel electrophoresis (DGGE) for mutation detection in Duchenne muscular dystrophy (DMD). Author(s): Dolinsky LC. Source: Methods in Molecular Biology (Clifton, N.J.). 2003; 217: 165-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12491931&dopt=Abstract

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Dental characteristics of patients with Duchenne muscular dystrophy. Author(s): Symons AL, Townsend GC, Hughes TE. Source: Asdc J Dent Child. 2002 September-December; 69(3): 277-83, 234. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12613312&dopt=Abstract

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Depressed myocardial fatty acid metabolism in patients with muscular dystrophy. Author(s): Momose M, Iguchi N, Imamura K, Usui H, Ueda T, Miyamoto K, Inaba S. Source: Neuromuscular Disorders : Nmd. 2001 July; 11(5): 464-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11404118&dopt=Abstract

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Detection of 1583 bp gene transcript in lymphocytes of muscular dystrophy patients. Author(s): Prabhakar S, Anand A. Source: Neurology India. 2002 December; 50(4): 537-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12577122&dopt=Abstract

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Detection of gene deletions in Chinese patients with Duchenne/Becker muscular dystrophy using CDNA probes and the polymerase chain reaction method. Author(s): Yuge L, Hui L, Bingdi X. Source: Life Sciences. 1999; 65(9): 863-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10465346&dopt=Abstract

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Deterioration of lung function and scoliosis in Duchenne muscular dystrophy. Author(s): Galasko SB. Source: Journal of Pediatric Orthopedics. 2001 November-December; 21(6): 827-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11675569&dopt=Abstract

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Developmental expression of myotilin, a gene mutated in limb-girdle muscular dystrophy type 1A. Author(s): Mologni L, Salmikangas P, Fougerousse F, Beckmann JS, Carpen O. Source: Mechanisms of Development. 2001 May; 103(1-2): 121-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11335118&dopt=Abstract

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Developments in gene therapy for muscular dystrophy. Author(s): Hartigan-O'Connor D, Chamberlain JS. Source: Microscopy Research and Technique. 2000 February 1-15; 48(3-4): 223-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10679969&dopt=Abstract

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Diaphragm kinetics during pneumatic belt respiratory assistance: a sonographic study in Duchenne muscular dystrophy. Author(s): Ayoub J, Milane J, Targhetta R, Prioux J, Chamari K, Arbeille P, Jonquet O, Bourgeois JM, Prefaut C. Source: Neuromuscular Disorders : Nmd. 2002 August; 12(6): 569-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117482&dopt=Abstract

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Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Author(s): Raffaele Di Barletta M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik KH, Merlini L, Trevisan C, Biancalana V, HousmanowaPetrusewicz I, Bione S, Ricotti R, Schwartz K, Bonne G, Toniolo D. Source: American Journal of Human Genetics. 2000 April; 66(4): 1407-12. Epub 2000 March 16. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10739764&dopt=Abstract


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Dilated cardiomyopathy of Becker-type muscular dystrophy with exon 4 deletion--a case report. Author(s): Saotome M, Yoshitomi Y, Kojima S, Kuramochi M. Source: Angiology. 2001 May; 52(5): 343-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11386386&dopt=Abstract

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Direct detection of 4q35 rearrangements implicated in facioscapulohumeral muscular dystrophy (FSHD). Author(s): Deidda G, Cacurri S, Piazzo N, Felicetti L. Source: Journal of Medical Genetics. 1996 May; 33(5): 361-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8733043&dopt=Abstract

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Disabilities in children with Duchenne muscular dystrophy: a profile. Author(s): Nair KP, Vasanth A, Gourie-Devi M, Taly AB, Rao S, Gayathri N, Murali T. Source: Journal of Rehabilitation Medicine : Official Journal of the Uems European Board of Physical and Rehabilitation Medicine. 2001 July; 33(4): 147-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11506211&dopt=Abstract

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Disability, coping and quality of life in individuals with muscular dystrophy: a prospective study over five years. Author(s): Natterlund B, Gunnarsson LG, Ahlstrom G. Source: Disability and Rehabilitation. 2000 November 20; 22(17): 776-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11194618&dopt=Abstract

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Disease taxonomy--monogenic muscular dystrophy. Author(s): Beckmann JS. Source: British Medical Bulletin. 1999; 55(2): 340-57. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10723861&dopt=Abstract

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Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. Author(s): Schroder R, Kunz WS, Rouan F, Pfendner E, Tolksdorf K, Kappes-Horn K, Altenschmidt-Mehring M, Knoblich R, van der Ven PF, Reimann J, Furst DO, Blumcke I, Vielhaber S, Zillikens D, Eming S, Klockgether T, Uitto J, Wiche G, Rolfs A. Source: Journal of Neuropathology and Experimental Neurology. 2002 June; 61(6): 52030. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12071635&dopt=Abstract

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Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy. Author(s): Herrmann R, Straub V, Blank M, Kutzick C, Franke N, Jacob EN, Lenard HG, Kroger S, Voit T. Source: Human Molecular Genetics. 2000 September 22; 9(15): 2335-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11001938&dopt=Abstract

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Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype. Author(s): Illa I, Serrano-Munuera C, Gallardo E, Lasa A, Rojas-Garcia R, Palmer J, Gallano P, Baiget M, Matsuda C, Brown RH. Source: Annals of Neurology. 2001 January; 49(1): 130-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11198284&dopt=Abstract

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Distal muscular dystrophy of the Miyoshi type. Author(s): Yildiz H, Emre U, Coskun O, Ergun U, Atasoy HT, Inan LE. Source: Clin Neuropathol. 2003 July-August; 22(4): 204-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12908758&dopt=Abstract

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Distinguishing cardiac features of a novel form of congenital muscular dystrophy (Salih cmd). Author(s): Subahi SA. Source: Pediatric Cardiology. 2001 July-August; 22(4): 297-301. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11455396&dopt=Abstract

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Do some genetic mutations predict the development of dilated cardiomyopathy in patients with Becker's muscular dystrophy? Author(s): Ozdemir O, Arda K, Soylu M, Kutuk E. Source: Angiology. 2003 May-June; 54(3): 383-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12785035&dopt=Abstract

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Down-regulation of an ankyrin repeat-containing protein, V-1, during skeletal muscle differentiation and its re-expression in the regenerative process of muscular dystrophy. Author(s): Furukawa Y, Hashimoto N, Yamakuni T, Ishida Y, Kato C, Ogashiwa M, Kobayashi M, Kobayashi T, Nonaka I, Mizusawa H, Song SY. Source: Neuromuscular Disorders : Nmd. 2003 January; 13(1): 32-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467730&dopt=Abstract

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Duchenne and Becker muscular dystrophy: from gene diagnosis to molecular therapy. Author(s): Matsuo M. Source: Iubmb Life. 2002 March; 53(3): 147-52. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12102170&dopt=Abstract


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Duchenne muscular dystrophy improved by gentamicin. Author(s): Senior K. Source: Molecular Medicine Today. 1999 November; 5(11): 461. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10529784&dopt=Abstract

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Duchenne muscular dystrophy in a female child. Author(s): Viswanathan V. Source: Indian Pediatrics. 2002 October; 39(10): 980-1; Author Reply 981. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12428052&dopt=Abstract

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Duchenne muscular dystrophy in a female child. Author(s): Joshi S. Source: Indian Pediatrics. 2002 January; 39(1): 98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11805363&dopt=Abstract

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Duchenne muscular dystrophy or Meryon's disease. Author(s): Emery A. Source: Lancet. 2001 May 12; 357(9267): 1529. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11383539&dopt=Abstract

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Duchenne muscular dystrophy. Author(s): Sussman M. Source: J Am Acad Orthop Surg. 2002 March-April; 10(2): 138-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11929208&dopt=Abstract

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Duchenne muscular dystrophy. Author(s): Metules T. Source: Rn. 2002 October; 65(10): 39-44, 47; Quiz 48. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12432710&dopt=Abstract

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Duchenne muscular dystrophy. Author(s): Ishikawa Y, Bach JR. Source: Thorax. 1999 June; 54(6): 564. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10866575&dopt=Abstract

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Duchenne muscular dystrophy. Author(s): Dickson G, Brown SC. Source: Mol Cell Biol Hum Dis Ser. 1995; 5: 261-80. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9532571&dopt=Abstract

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Duchenne muscular dystrophy. See me graduate. Author(s): Verberkt HJ. Source: Lancet. 2001 December; 358 Suppl: S26. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11784575&dopt=Abstract

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Duchenne muscular dystrophy: current knowledge, treatment, and future prospects. Author(s): Biggar WD, Klamut HJ, Demacio PC, Stevens DJ, Ray PN. Source: Clinical Orthopaedics and Related Research. 2002 August; (401): 88-106. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12151886&dopt=Abstract

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Duchenne muscular dystrophy: lack of differences in the expression of endogenous carbohydrate- and heparin-binding proteins (lectins) in cultured fibroblasts. Author(s): Stulnig T, Schweiger M, Hirsch-Kauffmann M. Source: European Journal of Cell Biology. 1993 October; 62(1): 173-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8269975&dopt=Abstract

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Duchenne muscular dystrophy: prolongation of life by noninvasive ventilation and mechanically assisted coughing. Author(s): Gomez-Merino E, Bach JR. Source: American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists. 2002 June; 81(6): 411-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12023596&dopt=Abstract

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Duchenne muscular dystrophy: relevant paper was not included. Author(s): Smith RA, Phillips RS. Source: Bmj (Clinical Research Ed.). 2001 November 24; 323(7323): 1253. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11719423&dopt=Abstract

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Duchenne muscular dystrophy-rhabdomyosarcoma, ichthyosis vulgaris/acute monoblastic leukemia: association of rare genetic disorders and childhood malignant diseases. Author(s): Jakab Z, Szegedi I, Balogh E, Kiss C, Olah E. Source: Medical and Pediatric Oncology. 2002 July; 39(1): 66-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12116087&dopt=Abstract

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Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations. Author(s): Pillers DM, Fitzgerald KM, Duncan NM, Rash SM, White RA, Dwinnell SJ, Powell BR, Schnur RE, Ray PN, Cibis GW, Weleber RG. Source: Human Genetics. 1999 July-August; 105(1-2): 2-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10480348&dopt=Abstract


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Duchenne/Becker muscular dystrophy: from molecular diagnosis to gene therapy. Author(s): Matsuo M. Source: Brain & Development. 1996 May-June; 18(3): 167-72. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8836495&dopt=Abstract

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Duchenne-Becker muscular dystrophy and the nondystrophic myotonias. Paradigms for loss of function and change of function of gene products. Author(s): Hoffman EP, Wang J. Source: Archives of Neurology. 1993 November; 50(11): 1227-37. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8215981&dopt=Abstract

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Duplication detection in Japanese Duchenne muscular dystrophy patients and identification of carriers with partial gene deletions using pulsed-field gel electrophoresis. Author(s): Kodaira M, Hiyama K, Karakawa T, Kameo H, Satoh C. Source: Human Genetics. 1993 October 1; 92(3): 237-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8406431&dopt=Abstract

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Dysferlin and muscular dystrophy. Author(s): Bushby KM. Source: Acta Neurol Belg. 2000 September; 100(3): 142-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11098285&dopt=Abstract

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Dysmyelinating sensory-motor neuropathy in merosin-deficient congenital muscular dystrophy. Author(s): Di Muzio A, De Angelis MV, Di Fulvio P, Ratti A, Pizzuti A, Stuppia L, Gambi D, Uncini A. Source: Muscle & Nerve. 2003 April; 27(4): 500-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12661054&dopt=Abstract

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Dystrophin and muscular dystrophy: past, present, and future. Author(s): O'Brien KF, Kunkel LM. Source: Molecular Genetics and Metabolism. 2001 September-October; 74(1-2): 75-88. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11592805&dopt=Abstract

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Dystrophinopathy in isolated female patients with muscular dystrophy. Author(s): Serdaroglu A, Kotiloglu E, Caglar M, Topaloglu H. Source: Pediatric Pathology & Laboratory Medicine : Journal of the Society for Pediatric Pathology, Affiliated with the International Paediatric Pathology Association. 1996 MayJune; 16(3): 393-402. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9025841&dopt=Abstract

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Early and severe presentation of autosomal dominant Emery-Dreifuss muscular dystrophy (EMD2). Author(s): Mercuri E, Manzur AY, Jungbluth H, Bonne G, Muchir A, Sewry C, Schwartz K, Muntoni F. Source: Neurology. 2000 April 25; 54(8): 1704-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10762524&dopt=Abstract

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Early cardiac failure in a child with Becker muscular dystrophy is due to an abnormally low amount of dystrophin transcript lacking exon 13. Author(s): Ishigaki C, Patria SY, Nishio H, Yoshioka A, Matsuo M. Source: Acta Paediatr Jpn. 1997 December; 39(6): 685-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9447758&dopt=Abstract

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Early decrease of IIx myosin heavy chain transcripts in Duchenne muscular dystrophy. Author(s): Pedemonte M, Sandri C, Schiaffino S, Minetti C. Source: Biochemical and Biophysical Research Communications. 1999 February 16; 255(2): 466-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10049732&dopt=Abstract

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Early diagnosis in Duchenne muscular dystrophy. Author(s): Zalaudek I, Bonelli RM, Koltringer P, Reisecker F, Wagner K. Source: Lancet. 1999 June 5; 353(9168): 1975. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10371601&dopt=Abstract

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Early diagnosis of Duchenne muscular dystrophy with high level of transaminases. Author(s): Kurul S, Ulgenalp A, Dirik E, Ercal D. Source: Indian Pediatrics. 2002 February; 39(2): 210-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11867860&dopt=Abstract

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Early observations on muscular dystrophy: Gowers' textbook revisited. Author(s): Pascuzzi RM. Source: Seminars in Neurology. 1999; 19(1): 87-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10711992&dopt=Abstract

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Early onset of cardiomyopathy in two brothers with X-linked Emery-Dreifuss muscular dystrophy. Author(s): Talkop UA, Talvik I, Sonajalg M, Sibul H, Kolk A, Piirsoo A, Warzok R, Wulff K, Wehnert MS, Talvik T. Source: Neuromuscular Disorders : Nmd. 2002 November; 12(9): 878-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12398842&dopt=Abstract


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Early onset of X-linked Emery-Dreifuss muscular dystrophy in a boy with emerin gene deletion. Author(s): Fujimoto S, Ishikawa T, Saito M, Wada Y, Wada I, Arahata K, Nonaka I. Source: Neuropediatrics. 1999 June; 30(3): 161-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10480214&dopt=Abstract

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Early onset, autosomal recessive muscular dystrophy with Emery-Dreifuss phenotype and normal emerin expression. Author(s): Taylor J, Sewry CA, Dubowitz V, Muntoni F. Source: Neurology. 1998 October; 51(4): 1116-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9781539&dopt=Abstract

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Early prednisone treatment in Duchenne muscular dystrophy. Author(s): Merlini L, Cicognani A, Malaspina E, Gennari M, Gnudi S, Talim B, Franzoni E. Source: Muscle & Nerve. 2003 February; 27(2): 222-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12548530&dopt=Abstract

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Early presentation of X-linked Emery-Dreifuss muscular dystrophy resembling limbgirdle muscular dystrophy. Author(s): Muntoni F, Lichtarowicz-Krynska EJ, Sewry CA, Manilal S, Recan D, Llense S, Taylor J, Morris GE, Dubowitz V. Source: Neuromuscular Disorders : Nmd. 1998 April; 8(2): 72-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9608559&dopt=Abstract

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Early symptoms of Duchenne muscular dystrophy--description of cases of an 18month-old and an 8-year-old patient. Author(s): Iwanczak F, Stawarski A, Potyrala M, Siedlecka-Dawidko J, Agrawal GS. Source: Medical Science Monitor : International Medical Journal of Experimental and Clinical Research. 2000 May-June; 6(3): 592-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11208376&dopt=Abstract

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Early ultrastructural changes in the central nervous system in Fukuyama congenital muscular dystrophy. Author(s): Yamamoto T, Shibata N, Kanazawa M, Kobayashi M, Komori T, Kondo E, Saito K, Osawa M. Source: Ultrastructural Pathology. 1997 July-August; 21(4): 355-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9206000&dopt=Abstract

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Early white matter changes on brain magnetic resonance imaging in a newborn affected by merosin-deficient congenital muscular dystrophy. Author(s): Mercuri E, Rutherford M, De Vile C, Counsell S, Sewry C, Brown S, Bydder G, Dubowitz V, Muntoni F. Source: Neuromuscular Disorders : Nmd. 2001 April; 11(3): 297-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11297945&dopt=Abstract

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Early-onset facioscapulohumeral muscular dystrophy: two case reports. Author(s): Okinaga A, Matsuoka T, Umeda J, Yanagihara I, Inui K, Nagai T, Okada S. Source: Brain & Development. 1997 December; 19(8): 563-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9440803&dopt=Abstract

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Effects of deflazacort on left ventricular function in patients with Duchenne muscular dystrophy. Author(s): Silversides CK, Webb GD, Harris VA, Biggar DW. Source: The American Journal of Cardiology. 2003 March 15; 91(6): 769-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12633823&dopt=Abstract

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Effects of deleting a tripeptide sequence observed in muscular dystrophy patients on the conformation of synthetic peptides corresponding to the scaffolding domain of caveolin-3. Author(s): Jagannadham MV, Sharadadevi A, Nagaraj R. Source: Biochemical and Biophysical Research Communications. 2002 October 25; 298(2): 203-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12387816&dopt=Abstract

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Effects of expressing lamin A mutant protein causing Emery-Dreifuss muscular dystrophy and familial partial lipodystrophy in HeLa cells. Author(s): Bechert K, Lagos-Quintana M, Harborth J, Weber K, Osborn M. Source: Experimental Cell Research. 2003 May 15; 286(1): 75-86. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12729796&dopt=Abstract

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Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy. Author(s): Zhang RZ, Sabatelli P, Pan TC, Squarzoni S, Mattioli E, Bertini E, Pepe G, Chu ML. Source: The Journal of Biological Chemistry. 2002 November 15; 277(46): 43557-64. Epub 2002 September 05. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12218063&dopt=Abstract


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Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy. Author(s): Ishii H, Hayashi YK, Nonaka I, Arahata K. Source: Neuromuscular Disorders : Nmd. 1997 May; 7(3): 191-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9185184&dopt=Abstract

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Electroretinogram in Duchenne/Becker muscular dystrophy. Author(s): Pascual Pascual SI, Molano J, Pascual-Castroviejo I. Source: Pediatric Neurology. 1998 April; 18(4): 315-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9588526&dopt=Abstract

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Electroretinographic findings in Duchenne/Becker muscular dystrophy and correlation with genotype. Author(s): Ulgenalp A, Oner FH, Soylev MF, Bora E, Afrashi F, Kose S, Ercal D. Source: Ophthalmic Genetics. 2002 September; 23(3): 157-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12324874&dopt=Abstract

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Elevated aminotransferase activity as an indication of muscular dystrophy: case reports and review of the literature. Author(s): Zamora S, Adams C, Butzner JD, Machida H, Scott RB. Source: Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. 1996 October; 10(6): 389-93. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9193775&dopt=Abstract

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Elevated plasma levels of transforming growth factor beta1 in patients with muscular dystrophy. Author(s): Ishitobi M, Haginoya K, Zhao Y, Ohnuma A, Minato J, Yanagisawa T, Tanabu M, Kikuchi M, Iinuma K. Source: Neuroreport. 2000 December 18; 11(18): 4033-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11192624&dopt=Abstract

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Emerin and cardiomyopathy in Emery-Dreifuss muscular dystrophy. Author(s): Funakoshi M, Tsuchiya Y, Arahata K. Source: Neuromuscular Disorders : Nmd. 1999 March; 9(2): 108-14. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10220866&dopt=Abstract

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Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane. Author(s): Yorifuji H, Tadano Y, Tsuchiya Y, Ogawa M, Goto K, Umetani A, Asaka Y, Arahata K. Source: Neurogenetics. 1997 September; 1(2): 135-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10732816&dopt=Abstract

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Emery-Dreifuss muscular dystrophy - a 40 year retrospective. Author(s): Emery AE. Source: Neuromuscular Disorders : Nmd. 2000 June; 10(4-5): 228-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10838246&dopt=Abstract

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Emery-Dreifuss muscular dystrophy, nuclear cell signaling and chromatin remodeling. Author(s): Maraldi NM, Squarzoni S, Sabatelli P, Lattanzi G, Ognibene A, Manzoli FA. Source: Advances in Enzyme Regulation. 2002; 42: 1-18. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12123703&dopt=Abstract

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Emery-Dreifuss muscular dystrophy. Author(s): Helbling-Leclerc A, Bonne G, Schwartz K. Source: European Journal of Human Genetics : Ejhg. 2002 March; 10(3): 157-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11973618&dopt=Abstract

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Emery-Dreifuss muscular dystrophy. Author(s): Zacharias AS, Wagener ME, Warren ST, Hopkins LC. Source: Seminars in Neurology. 1999; 19(1): 67-79. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10711990&dopt=Abstract

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Emery-Dreifuss muscular dystrophy: anatomical-clinical correlation (case report). Author(s): Carvalho AA, Levy JA, Gutierrez PS, Marie SK, Sosa EA, Scanavaca M. Source: Arquivos De Neuro-Psiquiatria. 2000 December; 58(4): 1123-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11105084&dopt=Abstract

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Enhanced expression of the alpha 7 beta 1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. Author(s): Burkin DJ, Wallace GQ, Nicol KJ, Kaufman DJ, Kaufman SJ. Source: The Journal of Cell Biology. 2001 March 19; 152(6): 1207-18. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11257121&dopt=Abstract

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Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel. Author(s): Blumen SC, Nisipeanu P, Sadeh M, Asherov A, Blumen N, Wirguin Y, Khilkevich O, Carasso RL, Korczyn AD. Source: Neuromuscular Disorders : Nmd. 1997 October; 7 Suppl 1: S38-40. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9392014&dopt=Abstract


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Epidermolysis bullosa simplex associated with muscular dystrophy: phenotypegenotype correlations and review of the literature. Author(s): Shimizu H, Takizawa Y, Pulkkinen L, Murata S, Kawai M, Hachisuka H, Udono M, Uitto J, Nishikawa T. Source: Journal of the American Academy of Dermatology. 1999 December; 41(6): 950-6. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10570379&dopt=Abstract

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Epidermolysis bullosa: novel and de novo premature termination codon and deletion mutations in the plectin gene predict late-onset muscular dystrophy. Author(s): Rouan F, Pulkkinen L, Meneguzzi G, Laforgia S, Hyde P, Kim DU, Richard G, Uitto J. Source: The Journal of Investigative Dermatology. 2000 February; 114(2): 381-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10652002&dopt=Abstract

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Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy. Author(s): Funakoshi M, Goto K, Arahata K. Source: Neurology. 1998 June; 50(6): 1791-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9633729&dopt=Abstract

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Epiphora as a presenting sign of facioscapulohumeral muscular dystrophy. Author(s): Funnell CL, George ND. Source: Journal of Pediatric Ophthalmology and Strabismus. 2003 March-April; 40(2): 113-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12691238&dopt=Abstract

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epsilon-Sarcoglycan, a broadly expressed homologue of the gene mutated in limbgirdle muscular dystrophy 2D. Author(s): Ettinger AJ, Feng G, Sanes JR. Source: The Journal of Biological Chemistry. 1997 December 19; 272(51): 32534-8. Erratum In: J Biol Chem 1998 July 31; 273(31): 19922. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9405466&dopt=Abstract

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ERG in Duchenne/Becker muscular dystrophy. Author(s): Fitzgerald KM, Cibis GW, White RA. Source: Pediatric Neurology. 1998 November; 19(5): 400-1. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9880152&dopt=Abstract

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ERG phenotype of a dystrophin mutation in heterozygous female carriers of Duchenne muscular dystrophy. Author(s): Fitzgerald KM, Cibis GW, Gettel AH, Rinaldi R, Harris DJ, White RA. Source: Journal of Medical Genetics. 1999 April; 36(4): 316-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10227401&dopt=Abstract

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Esophageal motility disorders in Mexican patients with Duchenne's muscular dystrophy. Author(s): Camelo AL, Awad RA, Madrazo A, Aguilar F, Award RA. Source: Acta Gastroenterol Latinoam. 1997; 27(3): 119-22. Erratum In: Acta Gastroenterol Latinoam 1998; 28(1): 46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9339236&dopt=Abstract

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Estimation of body composition in muscular dystrophy by MRI and stereology. Author(s): Gong QY, Phoenix J, Kemp GJ, Garcia-Finana M, Frostick SP, Brodie DA, Edwards RH, Whitehouse GH, Roberts N. Source: Journal of Magnetic Resonance Imaging : Jmri. 2000 September; 12(3): 467-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10992315&dopt=Abstract

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Evaluation of a program for long-term treatment of Duchenne muscular dystrophy. Experience at the University Hospitals of Cleveland. Author(s): Vignos PJ, Wagner MB, Karlinchak B, Katirji B. Source: The Journal of Bone and Joint Surgery. American Volume. 1996 December; 78(12): 1844-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8986661&dopt=Abstract

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Evaluation of dysrhythmia in children with muscular dystrophy. Author(s): Oguz D, Olgunturk R, Tunaoglu FS, Gucuyener K, Kose G, Unlu M. Source: Angiology. 2000 November; 51(11): 925-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11103861&dopt=Abstract

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Evaluation of microchip electrophoresis as a molecular diagnostic method for Duchenne muscular dystrophy. Author(s): Ferrance J, Snow K, Landers JP. Source: Clinical Chemistry. 2002 February; 48(2): 380-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11805028&dopt=Abstract

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Evaluation of the facioscapulohumeral muscular dystrophy (FSHD1) phenotype in correlation to the concurrence of 4q35 and 10q26 fragments. Author(s): Kohler J, Rohrig D, Bathke KD, Koch MC. Source: Clinical Genetics. 1999 February; 55(2): 88-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10189085&dopt=Abstract


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Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Author(s): Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M, King W, Weiffenbach B, Figlewicz D. Source: Annals of Neurology. 1996 June; 39(6): 744-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8651646&dopt=Abstract

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Evidence for anticipation in autosomal dominant limb-girdle muscular dystrophy. Author(s): Speer MC, Gilchrist JM, Stajich JM, Gaskell PC, Westbrook CA, Horrigan SK, Bartoloni L, Yamaoka LH, Scott WK, Pericak-Vance MA. Source: Journal of Medical Genetics. 1998 April; 35(4): 305-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9598725&dopt=Abstract

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Evidence of left ventricular dysfunction in children with merosin-deficient congenital muscular dystrophy. Author(s): Spyrou N, Philpot J, Foale R, Camici PG, Muntoni F. Source: American Heart Journal. 1998 September; 136(3): 474-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9736139&dopt=Abstract

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Evoked potential study in facio-scapulo-humeral muscular dystrophy. Author(s): Fierro B, Daniele O, Aloisio A, Buffa D, La Bua V, Oliveri M, Manfre L, Brighina F. Source: Acta Neurologica Scandinavica. 1997 June; 95(6): 346-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9228268&dopt=Abstract

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Evolution of cardiac abnormalities in Becker muscular dystrophy over a 13-year period. Author(s): Hoogerwaard EM, de Voogt WG, Wilde AA, van der Wouw PA, Bakker E, van Ommen GJ, de Visser M. Source: Journal of Neurology. 1997 October; 244(10): 657-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9402544&dopt=Abstract

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Examination of telomere lengths in muscle tissue casts doubt on replicative aging as cause of progression in Duchenne muscular dystrophy. Author(s): Oexle K, Zwirner A, Freudenberg K, Kohlschutter A, Speer A. Source: Pediatric Research. 1997 August; 42(2): 226-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9262227&dopt=Abstract

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Exclusion of identified LGMD1 loci from four dominant limb-girdle muscular dystrophy families. Author(s): Speer MC, Vance JM, Lennon-Graham F, Stajich JM, Viles KD, Gilchrist JM, Nigro V, McMichael R, Chutkow JG, Bartoloni L, Horrigan SK, Westbrook CA, PericakVance MA. Source: Human Heredity. 1998 July-August; 48(4): 179-84. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9694248&dopt=Abstract

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Exclusion of muscle specific actinin-associated LIM protein (ALP) gene from 4q35 facioscapulohumeral muscular dystrophy (FSHD) candidate genes. Author(s): Bouju S, Pietu G, Le Cunff M, Cros N, Malzac P, Pellissier JF, Pons F, Leger JJ, Auffray C, Dechesne CA. Source: Neuromuscular Disorders : Nmd. 1999 January; 9(1): 3-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10063829&dopt=Abstract

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Expression and distribution of a small-conductance calcium-activated potassium channel (SK3) protein in skeletal muscles from myotonic muscular dystrophy patients and congenital myotonic mice. Author(s): Kimura T, Takahashi MP, Fujimura H, Sakoda S. Source: Neuroscience Letters. 2003 August 28; 347(3): 191-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12875918&dopt=Abstract

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Expression and localization of protein inhibitor of neuronal nitric oxide synthase in Duchenne muscular dystrophy. Author(s): Guo Y, Petrof BJ, Hussain SN. Source: Muscle & Nerve. 2001 November; 24(11): 1468-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11745948&dopt=Abstract

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Expression of lamin A mutated in the carboxyl-terminal tail generates an aberrant nuclear phenotype similar to that observed in cells from patients with Dunnigan-type partial lipodystrophy and Emery-Dreifuss muscular dystrophy. Author(s): Favreau C, Dubosclard E, Ostlund C, Vigouroux C, Capeau J, Wehnert M, Higuet D, Worman HJ, Courvalin JC, Buendia B. Source: Experimental Cell Research. 2003 January 1; 282(1): 14-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490190&dopt=Abstract

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Expression of laminin chains in skin in merosin-deficient congenital muscular dystrophy. Author(s): Sewry CA, D'Alessandro M, Wilson LA, Sorokin LM, Naom I, Bruno S, Ferlini A, Dubowitz V, Muntoni F. Source: Neuropediatrics. 1997 August; 28(4): 217-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9309712&dopt=Abstract


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Expression of plectin and HD1 epitopes in patients with epidermolysis bullosa simplex associated with muscular dystrophy. Author(s): Shimizu H, Masunaga T, Kurihara Y, Owaribe K, Wiche G, Pulkkinen L, Uitto J, Nishikawa T. Source: Archives of Dermatological Research. 1999 October; 291(10): 531-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10552210&dopt=Abstract

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Extraosseous uptake of Tc-99m HDP in muscular dystrophy. Author(s): Nye PJ, Aelion JA, Odhav SK, Bain S. Source: Clinical Nuclear Medicine. 2000 February; 25(2): 135-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10656652&dopt=Abstract

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Facial structure and functional findings in patients with progressive muscular dystrophy (Duchenne). Author(s): Eckardt L, Harzer W. Source: American Journal of Orthodontics and Dentofacial Orthopedics : Official Publication of the American Association of Orthodontists, Its Constituent Societies, and the American Board of Orthodontics. 1996 August; 110(2): 185-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8760845&dopt=Abstract

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Facioscapulohumeral (FSHD1) and other forms of muscular dystrophy in the same family: is there more in muscular dystrophy than meets the eye? Author(s): Tonini MM, Passos-Bueno MR, Cerqueira A, Pavanello R, Vainzof M, Dubowitz V, Zatz M. Source: Neuromuscular Disorders : Nmd. 2002 August; 12(6): 554-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12117479&dopt=Abstract

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Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress. Author(s): Winokur ST, Barrett K, Martin JH, Forrester JR, Simon M, Tawil R, Chung SA, Masny PS, Figlewicz DA. Source: Neuromuscular Disorders : Nmd. 2003 May; 13(4): 322-33. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12868502&dopt=Abstract

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Facioscapulohumeral muscular dystrophy (FSHD): design of natural history study and results of baseline testing. FSH-DY Group. Author(s): Tawil R, McDermott MP, Mendell JR, Kissel J, Griggs RC. Source: Neurology. 1994 March; 44(3 Pt 1): 442-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8145913&dopt=Abstract

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Facioscapulohumeral muscular dystrophy and myasthenia gravis co-existing in the same patient: a case report. Author(s): McGonigal A, Thomas AM, Petty RK. Source: Journal of Neurology. 2002 February; 249(2): 219-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11985390&dopt=Abstract

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Facioscapulohumeral muscular dystrophy in early childhood. Author(s): Brouwer OF, Padberg GW, Wijmenga C, Frants RR. Source: Archives of Neurology. 1994 April; 51(4): 387-94. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8155016&dopt=Abstract

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Facioscapulohumeral muscular dystrophy in the Dutch population. Author(s): Padberg GW, Frants RR, Brouwer OF, Wijmenga C, Bakker E, Sandkuijl LA. Source: Muscle & Nerve. 1995; 2: S81-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7739631&dopt=Abstract

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Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Author(s): Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM. Source: Nature Genetics. 2002 October; 32(2): 235-6. Epub 2002 September 23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12355084&dopt=Abstract

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Facioscapulohumeral muscular dystrophy presenting isolated monomelic lower limb atrophy. Report of two patients with and without 4q35 rearrangement. Author(s): Uncini A, Galluzzi G, Di Muzio A, De Angelis MV, Ricci E, Scoppetta C, Servidei S. Source: Neuromuscular Disorders : Nmd. 2002 November; 12(9): 874-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12398841&dopt=Abstract

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Facioscapulohumeral muscular dystrophy with chromosome 9p deletion. Author(s): Ueyama H, Kumamoto T, Mita S, Kimura E, Nakagawa M, Uchino M, Ando M. Source: Neurology. 1996 February; 46(2): 566-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8614537&dopt=Abstract

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Facioscapulohumeral muscular dystrophy with EcoRI/BlnI fragment size of more than 32 kb. Author(s): Vielhaber S, Jakubiczka S, Schroder JM, Sailer M, Feistner H, Heinze HJ, Wieacker P, Bettecken T. Source: Muscle & Nerve. 2002 April; 25(4): 540-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11932972&dopt=Abstract


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Facioscapulohumeral muscular dystrophy. Author(s): Fitzsimons RB. Source: Current Opinion in Neurology. 1999 October; 12(5): 501-11. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10590886&dopt=Abstract

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Facioscapulohumeral muscular dystrophy: clinical diversity and genetic abnormalities in Japanese patients. Author(s): Nakagawa M, Matsuzaki T, Higuchi I, Fukunaga H, Inui T, Nagamitsu S, Yamada H, Arimura K, Osame M. Source: Intern Med. 1997 May; 36(5): 333-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9213170&dopt=Abstract

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Failure of early diagnosis in symptomatic Duchenne muscular dystrophy. Author(s): Bushby KM, Hill A, Steele JG. Source: Lancet. 1999 February 13; 353(9152): 557-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10028989&dopt=Abstract

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Familial arachnoid cysts associated with oculopharyngeal muscular dystrophy. Author(s): Jadeja KJ, Grewal RP. Source: Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia. 2003 January; 10(1): 125-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12464544&dopt=Abstract

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Familial concordance of brain magnetic resonance imaging changes in congenital muscular dystrophy. Author(s): Philpot J, Topaloglu H, Pennock J, Dubowitz V. Source: Neuromuscular Disorders : Nmd. 1995 May; 5(3): 227-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7633188&dopt=Abstract

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Familial facioscapulohumeral muscular dystrophy: phenotypic diversity and genetic abnormality. Author(s): Nakagawa M, Higuchi I, Yoshidome H, Isashiki Y, Ohkubo R, Kaseda S, Iwaki H, Fukunaga H, Osame M. Source: Acta Neurologica Scandinavica. 1996 February-March; 93(2-3): 189-92. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8741141&dopt=Abstract

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Feeding problems in merosin deficient congenital muscular dystrophy. Author(s): Philpot J, Bagnall A, King C, Dubowitz V, Muntoni F. Source: Archives of Disease in Childhood. 1999 June; 80(6): 542-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10332004&dopt=Abstract

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Fetal muscle biopsy as a diagnostic tool in Duchenne muscular dystrophy. Author(s): Nevo Y, Shomrat R, Yaron Y, Orr-Urtreger A, Harel S, Legum C. Source: Prenatal Diagnosis. 1999 October; 19(10): 921-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10521816&dopt=Abstract

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First meeting of the Duchenne Parent Project in Europe: Treatment of Duchenne Muscular Dystrophy. 7-8 November 1997, Rotterdam, The Netherlands. Author(s): Scheuerbrandt G. Source: Neuromuscular Disorders : Nmd. 1998 May; 8(3-4): 213-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9631405&dopt=Abstract

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Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD). Author(s): Kobayashi K, Nakahori Y, Mizuno K, Miyake M, Kumagai T, Honma A, Nonaka I, Nakamura Y, Tokunaga K, Toda T. Source: Human Genetics. 1998 September; 103(3): 323-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9799088&dopt=Abstract

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Four novel dystrophin point mutations: detection by protein truncation test and transcript analysis in lymphocytes from Duchenne muscular dystrophy patients. Author(s): Tuffery S, Bareil C, Demaille J, Claustres M. Source: European Journal of Human Genetics : Ejhg. 1996; 4(3): 143-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8840114&dopt=Abstract

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Four novel plectin gene mutations in Japanese patients with epidermolysis bullosa with muscular dystrophy disclosed by heteroduplex scanning and protein truncation tests. Author(s): Takizawa Y, Shimizu H, Rouan F, Kawai M, Udono M, Pulkkinen L, Nishikawa T, Uitto J. Source: The Journal of Investigative Dermatology. 1999 January; 112(1): 109-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9886273&dopt=Abstract

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Fracture prevalence in Duchenne muscular dystrophy. Author(s): McDonald DG, Kinali M, Gallagher AC, Mercuri E, Muntoni F, Roper H, Jardine P, Jones DH, Pike MG. Source: Developmental Medicine and Child Neurology. 2002 October; 44(10): 695-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12418795&dopt=Abstract

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Fracture risk in patients with muscular dystrophy and spinal muscular atrophy. Author(s): Vestergaard P, Glerup H, Steffensen BF, Rejnmark L, Rahbek J, Moseklide L. Source: Journal of Rehabilitation Medicine : Official Journal of the Uems European Board of Physical and Rehabilitation Medicine. 2001 July; 33(4): 150-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11506212&dopt=Abstract


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Frameshift deletions of exons 3-7 and revertant fibers in Duchenne muscular dystrophy: mechanisms of dystrophin production. Author(s): Winnard AV, Mendell JR, Prior TW, Florence J, Burghes AH. Source: American Journal of Human Genetics. 1995 January; 56(1): 158-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7825572&dopt=Abstract

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Free radicals, programmed cell death and muscular dystrophy. Author(s): Brown RH. Source: Current Opinion in Neurology. 1995 October; 8(5): 373-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8542043&dopt=Abstract

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Freeze-fracture analysis of muscle plasma membrane in Becker's muscular dystrophy. Author(s): Shibuya S, Wakayama Y, Jimi T, Oniki H, Kobayashi T, Misugi N, Kumagai T, Hasegawa O, Suzuki Y, Kuroiwa Y. Source: Neuropathology and Applied Neurobiology. 1994 October; 20(5): 487-94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7845534&dopt=Abstract

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Frequent low penetrance mutations in the Lamin A/C gene, causing Emery Dreifuss muscular dystrophy. Author(s): Vytopil M, Ricci E, Dello Russo A, Hanisch F, Neudecker S, Zierz S, Ricotti R, Demay L, Richard P, Wehnert M, Bonne G, Merlini L, Toniolo D. Source: Neuromuscular Disorders : Nmd. 2002 December; 12(10): 958-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467752&dopt=Abstract

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FRG1, a gene in the FSH muscular dystrophy region on human chromosome 4q35, is highly conserved in vertebrates and invertebrates. Author(s): Grewal PK, Todd LC, van der Maarel S, Frants RR, Hewitt JE. Source: Gene. 1998 August 17; 216(1): 13-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9714712&dopt=Abstract

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From dystrophinopathy to sarcoglycanopathy: evolution of a concept of muscular dystrophy. Author(s): Ozawa E, Noguchi S, Mizuno Y, Hagiwara Y, Yoshida M. Source: Muscle & Nerve. 1998 April; 21(4): 421-38. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9533777&dopt=Abstract

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Fukutin expression in glial cells and neurons: implication in the brain lesions of Fukuyama congenital muscular dystrophy. Author(s): Yamamoto T, Kato Y, Karita M, Takeiri H, Muramatsu F, Kobayashi M, Saito K, Osawa M. Source: Acta Neuropathologica. 2002 September; 104(3): 217-24. Epub 2002 June 21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12172906&dopt=Abstract

Studies 155

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Fukutin protein is expressed in neurons of the normal developing human brain but is reduced in Fukuyama-type congenital muscular dystrophy brain. Author(s): Saito Y, Mizuguchi M, Oka A, Takashima S. Source: Annals of Neurology. 2000 June; 47(6): 756-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10852541&dopt=Abstract

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Fukuyama congenital muscular dystrophy: a neuroradiologic review. Author(s): Aida N. Source: Journal of Magnetic Resonance Imaging : Jmri. 1998 March-April; 8(2): 317-26. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9562058&dopt=Abstract

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Fukuyama muscular dystrophy associated with lack of C-terminal domain of dystrophin. Author(s): Tachi N, Chiba S, Matsuo M, Matsumura K, Saito K. Source: Pediatric Neurology. 2001 May; 24(5): 373-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11516613&dopt=Abstract

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Fukuyama-type congenital muscular dystrophy: a case report in the Japanese population living in Brazil. Author(s): Zanoteli E, Rocha JC, Narumia LK, Fireman MA, Moura LS, Oliveira AS, Gabbai AA, Fukuda Y, Kinoshita M, Toda T. Source: Acta Neurologica Scandinavica. 2002 August; 106(2): 117-21. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12100373&dopt=Abstract

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Fukuyama-type congenital muscular dystrophy: close relation between changes in the muscle basal lamina and plasma membrane. Author(s): Matsubara S, Mizuno Y, Kitaguchi T, Isozaki E, Miyamoto K, Hirai S. Source: Neuromuscular Disorders : Nmd. 1999 October; 9(6-7): 388-98. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10545042&dopt=Abstract

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Fukuyama-type congenital muscular dystrophy: the first human disease to be caused by an ancient retrotransposal integration. Author(s): Toda T, Kobayashi K. Source: Journal of Molecular Medicine (Berlin, Germany). 1999 December; 77(12): 816-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10682317&dopt=Abstract


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Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A. Author(s): Ono Y, Shimada H, Sorimachi H, Richard I, Saido TC, Beckmann JS, Ishiura S, Suzuki K. Source: The Journal of Biological Chemistry. 1998 July 3; 273(27): 17073-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9642272&dopt=Abstract

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Functional domains of the nucleus: implications for Emery-Dreifuss muscular dystrophy. Author(s): Maraldi NM, Lattanzi G, Sabatelli P, Ognibene A, Squarzoni S. Source: Neuromuscular Disorders : Nmd. 2002 November; 12(9): 815-23. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12398831&dopt=Abstract

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Functional involvement of cerebral cortex in Duchenne muscular dystrophy. Author(s): Di Lazzaro V, Restuccia D, Servidei S, Nardone R, Oliviero A, Profice P, Mangiola F, Tonali P, Rothwell JC. Source: Muscle & Nerve. 1998 May; 21(5): 662-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9572251&dopt=Abstract

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Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Author(s): Sander M, Chavoshan B, Harris SA, Iannaccone ST, Stull JT, Thomas GD, Victor RG. Source: Proceedings of the National Academy of Sciences of the United States of America. 2000 December 5; 97(25): 13818-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11087833&dopt=Abstract

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Functional significance of dystrophin-positive fibers in Duchenne and Becker muscular dystrophy. Author(s): Tasdemir HA, Kotiloglu E, Topaloglu H, Kale G, Dincer DP, Yalaz K, Renda Y. Source: Pediatric Pathology & Laboratory Medicine : Journal of the Society for Pediatric Pathology, Affiliated with the International Paediatric Pathology Association. 1996 JulyAugust; 16(4): 583-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9025855&dopt=Abstract

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gamma-sarcoglycan deficiency muscular dystrophy in two adults. Author(s): Lin KL, Wang HS, Chen ST, Ro LS. Source: J Formos Med Assoc. 2000 October; 99(10): 789-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11061077&dopt=Abstract

Studies 157

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Gastric emptying time in children with progressive muscular dystrophy. Author(s): Okan M, Alper E, Cil E, Eralp O, Agir H. Source: Turk J Pediatr. 1997 January-March; 39(1): 69-74. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10868196&dopt=Abstract

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Gastric wall weakening resulting in separate perforations in a patient with Duchenne's muscular dystrophy. Author(s): Dinan D, Levine MS, Gordon AR, Rubesin SE, Rombeau JL. Source: Ajr. American Journal of Roentgenology. 2003 September; 181(3): 807-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12933486&dopt=Abstract

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Gastroparesis associated with muscular dystrophy. Author(s): Rohira SK, Bianco JA. Source: Clinical Nuclear Medicine. 1993 November; 18(11): 996. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8269689&dopt=Abstract

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GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy. Author(s): Mirabella M, Silvestri G, de Rosa G, Di Giovanni S, Di Muzio A, Uncini A, Tonali P, Servidei S. Source: Neurology. 2000 February 8; 54(3): 608-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10680791&dopt=Abstract

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GCG repeats and phenotype in oculopharyngeal muscular dystrophy. Author(s): Muller T, Schroder R, Zierz S. Source: Muscle & Nerve. 2001 January; 24(1): 120-2. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11150975&dopt=Abstract

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Gene deletion and carrier detection in the family of Becker muscular dystrophy by short tandem repeat sequence polymorphism. Author(s): Cai S, Shen D, Wang J. Source: Chin Med J (Engl). 1999 March; 112(3): 242-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11593558&dopt=Abstract

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Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle. Author(s): Haslett JN, Sanoudou D, Kho AT, Bennett RR, Greenberg SA, Kohane IS, Beggs AH, Kunkel LM. Source: Proceedings of the National Academy of Sciences of the United States of America. 2002 November 12; 99(23): 15000-5. Epub 2002 Nov 01. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12415109&dopt=Abstract


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Gene removes muscular dystrophy symptoms in mouse model. Author(s): Senior K. Source: Lancet. 2001 September 22; 358(9286): 990. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11583760&dopt=Abstract

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Gene therapy in Duchenne muscular dystrophy. Author(s): Inui K, Okada S, Dickson G. Source: Brain & Development. 1996 September-October; 18(5): 357-61. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8891229&dopt=Abstract

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Gene therapy of Duchenne muscular dystrophy. Author(s): Fassati A, Murphy S, Dickson G. Source: Adv Genet. 1997; 35: 117-53. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9348647&dopt=Abstract

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Gene therapy of muscular dystrophy. Author(s): Chamberlain JS. Source: Human Molecular Genetics. 2002 October 1; 11(20): 2355-62. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12351570&dopt=Abstract

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Gene therapy prospects for Duchenne muscular dystrophy. Author(s): Clemens PR, Caskey CT. Source: European Neurology. 1994; 34(4): 181-5. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8082675&dopt=Abstract

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Genealogical study of oculopharyngeal muscular dystrophy in France. Author(s): Brunet G, Tome FM, Eymard B, Robert JM, Fardeau M. Source: Neuromuscular Disorders : Nmd. 1997 October; 7 Suppl 1: S34-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9392013&dopt=Abstract

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Generation of a 3-Mb PAC contig spanning the Miyoshi myopathy/limb-girdle muscular dystrophy (MM/LGMD2B) locus on chromosome 2p13. Author(s): Liu J, Wu C, Bossie K, Bejaoui K, Hosler BA, Gingrich JC, Ben Hamida M, Hentati F, Schurr E, de Jong PJ, Brown RH Jr. Source: Genomics. 1998 April 1; 49(1): 23-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9570945&dopt=Abstract

Studies 159

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Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei. Author(s): Pegoraro E, Schimke RN, Garcia C, Stern H, Cadaldini M, Angelini C, Barbosa E, Carroll J, Marks WA, Neville HE. Source: Neurology. 1995 April; 45(4): 677-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7723955&dopt=Abstract

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Genetic and physical mapping at the limb-girdle muscular dystrophy locus (LGMD2B) on chromosome 2p. Author(s): Bashir R, Keers S, Strachan T, Passos-Bueno R, Zatz M, Weissenbach J, Le Paslier D, Meisler M, Bushby K. Source: Genomics. 1996 April 1; 33(1): 46-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8617508&dopt=Abstract

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Genetic counseling for childless women at risk for Duchenne muscular dystrophy. Author(s): Eggers S, Pavanello RC, Passos-Bueno MR, Zatz M. Source: American Journal of Medical Genetics. 1999 October 29; 86(5): 447-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10508987&dopt=Abstract

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Genetic counseling of isolated carriers of Duchenne muscular dystrophy. Author(s): Hoffman EP, Pegoraro E, Scacheri P, Burns RG, Taber JW, Weiss L, Spiro A, Blattner P. Source: American Journal of Medical Genetics. 1996 June 28; 63(4): 573-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8826437&dopt=Abstract

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Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy. Author(s): Mostacciuolo ML, Miorin M, Martinello F, Angelini C, Perini P, Trevisan CP. Source: Human Genetics. 1996 March; 97(3): 277-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8786062&dopt=Abstract

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Genetic epidemiology of Duchenne and Becker muscular dystrophy in Slovenia. Author(s): Peterlin B, Zidar J, Meznaric-Petrusa M, Zupancic N. Source: Clinical Genetics. 1997 February; 51(2): 94-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9111995&dopt=Abstract

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Genetic heterogeneity for Duchenne-like muscular dystrophy (DLMD) based on linkage and 50 DAG analysis. Author(s): Passos-Bueno MR, Oliveira JR, Bakker E, Anderson RD, Marie SK, Vainzof M, Roberds S, Campbell KP, Zatz M. Source: Human Molecular Genetics. 1993 November; 2(11): 1945-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8281158&dopt=Abstract


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Genetic heterogeneity in Miyoshi-type distal muscular dystrophy. Author(s): Linssen WH, de Visser M, Notermans NC, Vreyling JP, Van Doorn PA, Wokke JH, Baas F, Bolhuis PA. Source: Neuromuscular Disorders : Nmd. 1998 June; 8(5): 317-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9673985&dopt=Abstract

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Genetic heterogeneity in three Chinese children with Fukuyama congenital muscular dystrophy. Author(s): Jong YJ, Kobayashi K, Toda T, Kondo E, Huang SC, Shen YZ, Nonaka I, Fukuyama Y. Source: Neuromuscular Disorders : Nmd. 2000 February; 10(2): 108-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10714585&dopt=Abstract

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Genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy in a genetic isolate (Amish) and evidence for a new locus. Author(s): Allamand V, Broux O, Bourg N, Richard I, Tischfield JA, Hodes ME, Conneally PM, Fardeau M, Jackson CE, Beckmann JS. Source: Human Molecular Genetics. 1995 March; 4(3): 459-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7795603&dopt=Abstract

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Genetic heterogeneity of congenital muscular dystrophy with rigid spine syndrome. Author(s): Moghadaszadeh B, Topaloglu H, Merlini L, Muntoni F, Estournet B, Sewry C, Naom I, Barois A, Fardeau M, Tome FM, Guicheney P. Source: Neuromuscular Disorders : Nmd. 1999 October; 9(6-7): 376-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10545040&dopt=Abstract

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Genetic heterogeneity of severe childhood autosomal recessive muscular dystrophy with adhalin (50 kDa dystrophin-associated glycoprotein) deficiency. Author(s): Romero NB, Tome FM, Leturcq F, el Kerch FE, Azibi K, Bachner L, Anderson RD, Roberds SL, Campbell KP, Fardeau M, et al. Source: Comptes Rendus De L'academie Des Sciences. Serie Iii, Sciences De La Vie. 1994 January; 317(1): 70-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7987694&dopt=Abstract

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Genetic identity of Fukuyama-type congenital muscular dystrophy and WalkerWarburg syndrome. Author(s): Toda T, Yoshioka M, Nakahori Y, Kanazawa I, Nakamura Y, Nakagome Y. Source: Annals of Neurology. 1995 January; 37(1): 99-101. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7818265&dopt=Abstract

Studies 161

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Genetic localization of a newly recognized autosomal dominant limb-girdle muscular dystrophy with cardiac involvement (LGMD1B) to chromosome 1q11-21. Author(s): van der Kooi AJ, van Meegen M, Ledderhof TM, McNally EM, de Visser M, Bolhuis PA. Source: American Journal of Human Genetics. 1997 April; 60(4): 891-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9106535&dopt=Abstract

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Genetic mapping and haplotype analysis of oculopharyngeal muscular dystrophy. Author(s): Grewal RP, Cantor R, Turner G, Grewal RK, Detera-Wadleigh SD. Source: Neuroreport. 1998 April 20; 9(6): 961-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9601650&dopt=Abstract

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Genetic polymorphism in muscle biopsies of Duchenne and Becker muscular dystrophy patients. Author(s): Anand A, Prabhakar S, Kaul D. Source: Neurology India. 1999 September; 47(3): 218-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10514583&dopt=Abstract

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Genetics of facioscapulohumeral muscular dystrophy: new mutations in sporadic cases. Author(s): Griggs RC, Tawil R, Storvick D, Mendell JR, Altherr MR. Source: Neurology. 1993 November; 43(11): 2369-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8232958&dopt=Abstract

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Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy: from identification of mutations to prenatal diagnosis. Author(s): Guicheney P, Vignier N, Helbling-Leclerc A, Nissinen M, Zhang X, Cruaud C, Lambert JC, Richelme C, Topaloglu H, Merlini L, Barois A, Schwartz K, Tome FM, Tryggvason K, Fardeau M. Source: Neuromuscular Disorders : Nmd. 1997 May; 7(3): 180-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9185182&dopt=Abstract

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Genomic screening for beta-sarcoglycan gene mutations: missense mutations may cause severe limb-girdle muscular dystrophy type 2E (LGMD 2E). Author(s): Bonnemann CG, Passos-Bueno MR, McNally EM, Vainzof M, de Sa Moreira E, Marie SK, Pavanello RC, Noguchi S, Ozawa E, Zatz M, Kunkel LM. Source: Human Molecular Genetics. 1996 December; 5(12): 1953-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8968749&dopt=Abstract

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Genotype and electroretinal heterogeneity in Duchenne muscular dystrophy. Author(s): Ino-ue M, Honda S, Nishio H, Matsuo M, Nakamura H, Yamamoto M. Source: Experimental Eye Research. 1997 December; 65(6): 861-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9441711&dopt=Abstract


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Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype. Author(s): Yates JR, Bagshaw J, Aksmanovic VM, Coomber E, McMahon R, Whittaker JL, Morrison PJ, Kendrick-Jones J, Ellis JA. Source: Neuromuscular Disorders : Nmd. 1999 May; 9(3): 159-65. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10382909&dopt=Abstract

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Genotype-phenotype correlation in Duchenne/Becker muscular dystrophy patients seen at Lucknow. Author(s): Mittal B, Singh V, Mishra S, Sinha S, Mittal RD, Chaturvedi LS, Danda S, Pradhan S, Agarwal SS. Source: The Indian Journal of Medical Research. 1997 January; 105: 32-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9029833&dopt=Abstract

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Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Author(s): Wagner KR, Hamed S, Hadley DW, Gropman AL, Burstein AH, Escolar DM, Hoffman EP, Fischbeck KH. Source: Annals of Neurology. 2001 June; 49(6): 706-11. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11409421&dopt=Abstract

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Germinal mosaicism in facioscapulohumeral muscular dystrophy (FSHD). Author(s): Upadhyaya M, Maynard J, Osborn M, Jardine P, Harper PS, Lunt P. Source: Muscle & Nerve. 1995; 2: S45-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7739625&dopt=Abstract

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Germline and somatic mosaicism in a female carrier of Duchenne muscular dystrophy. Author(s): Bunyan DJ, Robinson DO, Collins AL, Cockwell AE, Bullman HM, Whittaker PA. Source: Human Genetics. 1994 May; 93(5): 541-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8168831&dopt=Abstract

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Germline mosaicism in 4q35 facioscapulohumeral muscular dystrophy (FSHD1A) occurring predominantly in oogenesis. Author(s): Kohler J, Rupilius B, Otto M, Bathke K, Koch MC. Source: Human Genetics. 1996 October; 98(4): 485-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8792827&dopt=Abstract

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Giant dystrophin deletion associated with congenital cataract and mild muscular dystrophy. Author(s): Mirabella M, Galluzzi G, Manfredi G, Bertini E, Ricci E, De Leo R, Tonali P, Servidei S. Source: Neurology. 1998 August; 51(2): 592-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9710043&dopt=Abstract

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Gradual onset of dysphagia: a study of patients with oculopharyngeal muscular dystrophy. Author(s): Young EC, Durant-Jones L. Source: Dysphagia. 1997 Fall; 12(4): 196-201. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9294939&dopt=Abstract

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Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy. Author(s): Saito K, Osawa M, Wang ZP, Ikeya K, Fukuyama Y, Kondo-Iida E, Toda T, Ohashi H, Kurosawa K, Wakai S, Kaneko K. Source: American Journal of Medical Genetics. 2000 May 29; 92(3): 184-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10817652&dopt=Abstract

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Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy. Author(s): Krag TO, Gyrd-Hansen M, Khurana TS. Source: Acta Physiologica Scandinavica. 2001 March; 171(3): 349-58. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11412148&dopt=Abstract

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Heart to heart: from nuclear proteins to Emery-Dreifuss muscular dystrophy. Author(s): Morris GE, Manilal S. Source: Human Molecular Genetics. 1999; 8(10): 1847-51. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10469836&dopt=Abstract

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Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. Author(s): Cartegni L, di Barletta MR, Barresi R, Squarzoni S, Sabatelli P, Maraldi N, Mora M, Di Blasi C, Cornelio F, Merlini L, Villa A, Cobianchi F, Toniolo D. Source: Human Molecular Genetics. 1997 December; 6(13): 2257-64. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9361031&dopt=Abstract

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Hemolytic anemia associated with myotonic muscular dystrophy. Author(s): Komeno T, Ninomiya H, Itoh T, Fujita T, Nagasawa T, Abe T. Source: Intern Med. 1996 September; 35(9): 746-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8915705&dopt=Abstract


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Hereditary ptosis of late onset: early observations on oculopharyngeal muscular dystrophy in Quebec by Roma Amyot. Author(s): Duquette P, Giard N. Source: Neuromuscular Disorders : Nmd. 1997 October; 7 Suppl 1: S12-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9392009&dopt=Abstract

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Heterogeneity in familial dominant Paget disease of bone and muscular dystrophy. Author(s): Waggoner B, Kovach MJ, Winkelman M, Cai D, Khardori R, Gelber D, Kimonis VE. Source: American Journal of Medical Genetics. 2002 March 15; 108(3): 187-91. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11891683&dopt=Abstract

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Heterogeneity of classic congenital muscular dystrophy with involvement of the central nervous system: report of five atypical cases. Author(s): Reed UC, Marie SK, Vainzof M, Gobbo LF, Gurgel JE, Carvalho MS, Resende MB, Espindola AA, Zatz M, Diament A. Source: Journal of Child Neurology. 2000 March; 15(3): 172-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10757473&dopt=Abstract

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Heterozygous myogenic factor 6 mutation associated with myopathy and severe course of Becker muscular dystrophy. Author(s): Kerst B, Mennerich D, Schuelke M, Stoltenburg-Didinger G, von Moers A, Gossrau R, van Landeghem FK, Speer A, Braun T, Hubner C. Source: Neuromuscular Disorders : Nmd. 2000 December; 10(8): 572-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11053684&dopt=Abstract

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High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy. Author(s): Connolly AM, Schierbecker J, Renna R, Florence J. Source: Neuromuscular Disorders : Nmd. 2002 December; 12(10): 917-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12467746&dopt=Abstract

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High frequency of de novo deletions in Mexican Duchenne and Becker muscular dystrophy patients. Implications for genetic counseling. Author(s): Alcantara MA, Villarreal MT, Del Castillo V, Gutierrez G, Saldana Y, Maulen I, Lee R, Macias M, Orozco L. Source: Clinical Genetics. 1999 May; 55(5): 376-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10422811&dopt=Abstract

Studies 165

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High frequency of new mutations in North Indian Duchenne/Becker muscular dystrophy patients. Author(s): Sinha S, Mishra S, Singh V, Mittal RD, Mittal B. Source: Clinical Genetics. 1996 November; 50(5): 327-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9007319&dopt=Abstract

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High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families. Author(s): Zatz M, Marie SK, Passos-Bueno MR, Vainzof M, Campiotto S, Cerqueira A, Wijmenga C, Padberg G, Frants R. Source: American Journal of Human Genetics. 1995 January; 56(1): 99-105. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7825608&dopt=Abstract

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High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q. Author(s): Bengtsson U, Altherr MR, Wasmuth JJ, Winokur ST. Source: Human Molecular Genetics. 1994 October; 3(10): 1801-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7849703&dopt=Abstract

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High resolution magnetic resonance imaging of the brain in the dy/dy mouse with merosin-deficient congenital muscular dystrophy. Author(s): Dubowitz DJ, Tyszka JM, Sewry CA, Moats RA, Scadeng M, Dubowitz V. Source: Neuromuscular Disorders : Nmd. 2000 June; 10(4-5): 292-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10838257&dopt=Abstract

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Hip subluxation and dislocation in Duchenne muscular dystrophy. Author(s): Chan KG, Galasko CS, Delaney C. Source: Journal of Pediatric Orthopaedics. Part B / European Paediatric Orthopaedic Society, Pediatric Orthopaedic Society of North America. 2001 July; 10(3): 219-25. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11497366&dopt=Abstract

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HnRNP A1 and A/B interaction with PABPN1 in oculopharyngeal muscular dystrophy. Author(s): Fan X, Messaed C, Dion P, Laganiere J, Brais B, Karpati G, Rouleau GA. Source: The Canadian Journal of Neurological Sciences. Le Journal Canadien Des Sciences Neurologiques. 2003 August; 30(3): 244-51. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12945950&dopt=Abstract


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Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease. Author(s): Blumen SC, Brais B, Korczyn AD, Medinsky S, Chapman J, Asherov A, Nisipeanu P, Codere F, Bouchard JP, Fardeau M, Tome FM, Rouleau GA. Source: Annals of Neurology. 1999 July; 46(1): 115-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10401788&dopt=Abstract

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Homozygous alpha-sarcoglycan mutation in two siblings: one asymptomatic and one steroid-responsive mild limb-girdle muscular dystrophy patient. Author(s): Angelini C, Fanin M, Menegazzo E, Freda MP, Duggan DJ, Hoffman EP. Source: Muscle & Nerve. 1998 June; 21(6): 769-75. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9585331&dopt=Abstract

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Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy. Author(s): Pulkkinen L, Smith FJ, Shimizu H, Murata S, Yaoita H, Hachisuka H, Nishikawa T, McLean WH, Uitto J. Source: Human Molecular Genetics. 1996 October; 5(10): 1539-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8894687&dopt=Abstract

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How the magnitude of clinical severity and recurrence risk affects reproductive decisions in adult males with different forms of progressive muscular dystrophy. Author(s): Eggers S, Zatz M. Source: Journal of Medical Genetics. 1998 March; 35(3): 189-95. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9541101&dopt=Abstract

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Human epsilon-sarcoglycan is highly related to alpha-sarcoglycan (adhalin), the limb girdle muscular dystrophy 2D gene. Author(s): McNally EM, Ly CT, Kunkel LM. Source: Febs Letters. 1998 January 23; 422(1): 27-32. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9475163&dopt=Abstract

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Hyperkalaemic cardiac arrest in a manifesting carrier of Duchenne muscular dystrophy following general anaesthesia. Author(s): Kerr TP, Duward A, Hodgson SV, Hughes E, Robb SA. Source: European Journal of Pediatrics. 2001 September; 160(9): 579-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11585084&dopt=Abstract

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Hyperkalaemic cardiac arrest. Patient may have had a muscular dystrophy or Andersen's syndrome. Author(s): Jardine P. Source: Bmj (Clinical Research Ed.). 1996 September 14; 313(7058): 692-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8811785&dopt=Abstract

Studies 167

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Hypoosmotic shocks induce elevation of resting calcium level in Duchenne muscular dystrophy myotubes contracting in vitro. Author(s): Imbert N, Vandebrouck C, Constantin B, Duport G, Guillou C, Cognard C, Raymond G. Source: Neuromuscular Disorders : Nmd. 1996 October; 6(5): 351-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8938699&dopt=Abstract

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Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression. Author(s): Tupler R, Barbierato L, Memmi M, Sewry CA, De Grandis D, Maraschio P, Tiepolo L, Ferlini A. Source: Journal of Medical Genetics. 1998 September; 35(9): 778-83. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9733041&dopt=Abstract

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Identical dysferlin mutation in limb-girdle muscular dystrophy type 2B and distal myopathy. Author(s): Illarioshkin SN, Ivanova-Smolenskaya IA, Greenberg CR, Nylen E, Sukhorukov VS, Poleshchuk VV, Markova ED, Wrogemann K. Source: Neurology. 2000 December 26; 55(12): 1931-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11134403&dopt=Abstract

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Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s). Author(s): Weiler T, Bashir R, Anderson LV, Davison K, Moss JA, Britton S, Nylen E, Keers S, Vafiadaki E, Greenberg CR, Bushby CR, Wrogemann K. Source: Human Molecular Genetics. 1999 May; 8(5): 871-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10196377&dopt=Abstract

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Identification and quantification of somatic mosaicism for a point mutation in a Duchenne muscular dystrophy family. Author(s): Smith TA, Yau SC, Bobrow M, Abbs SJ. Source: Journal of Medical Genetics. 1999 April; 36(4): 313-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10227400&dopt=Abstract

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Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7. Author(s): Speer MC, Vance JM, Grubber JM, Lennon Graham F, Stajich JM, Viles KD, Rogala A, McMichael R, Chutkow J, Goldsmith C, Tim RW, Pericak-Vance MA. Source: American Journal of Human Genetics. 1999 February; 64(2): 556-62. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9973293&dopt=Abstract


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Identification of a new locus for a peculiar form of congenital muscular dystrophy with early rigidity of the spine, on chromosome 1p35-36. Author(s): Moghadaszadeh B, Desguerre I, Topaloglu H, Muntoni F, Pavek S, Sewry C, Mayer M, Fardeau M, Tome FM, Guicheney P. Source: American Journal of Human Genetics. 1998 June; 62(6): 1439-45. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9585610&dopt=Abstract

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Identification of a novel truncating mutation (S171X) in the Emerin gene in five members of a Caucasian American family with Emery-Dreifuss muscular dystrophy. Author(s): Menache CC, Brown CA, Donnelly JH, Shapiro F, Darras BT. Source: Human Mutation. 2000 July; 16(1): 94. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10874323&dopt=Abstract

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Identification of altered gene expression in skeletal muscles from Duchenne muscular dystrophy patients. Author(s): Tkatchenko AV, Pietu G, Cros N, Gannoun-Zaki L, Auffray C, Leger JJ, Dechesne CA. Source: Neuromuscular Disorders : Nmd. 2001 April; 11(3): 269-77. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11297942&dopt=Abstract

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Identification of carriers of Duchenne/Becker muscular dystrophy by a novel method based on detection of junction fragments in the dystrophin gene. Author(s): Yamagishi H, Kato S, Hiraishi Y, Ishihara T, Hata J, Matsuo N, Takano T. Source: Journal of Medical Genetics. 1996 December; 33(12): 1027-31. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9004137&dopt=Abstract

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Identification of lamin A/C ( LMNA) gene mutations in Korean patients with autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy 1B. Author(s): Ki CS, Hong JS, Jeong GY, Ahn KJ, Choi KM, Kim DK, Kim JW. Source: Journal of Human Genetics. 2002; 47(5): 225-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12032588&dopt=Abstract

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Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Author(s): Muchir A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA, de Visser M, Schwartz K. Source: Human Molecular Genetics. 2000 May 22; 9(9): 1453-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10814726&dopt=Abstract

Studies 169

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Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease. Author(s): Bione S, Small K, Aksmanovic VM, D'Urso M, Ciccodicola A, Merlini L, Morandi L, Kress W, Yates JR, Warren ST, et al. Source: Human Molecular Genetics. 1995 October; 4(10): 1859-63. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8595407&dopt=Abstract

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Identification of novel mutations in three families with Emery-Dreifuss muscular dystrophy. Author(s): Klauck SM, Wilgenbus P, Yates JR, Muller CR, Poustka A. Source: Human Molecular Genetics. 1995 October; 4(10): 1853-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8595406&dopt=Abstract

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Immature astrocytes in Fukuyama congenital muscular dystrophy: an immunohistochemical study. Author(s): Yamamoto T, Armstrong D, Shibata N, Kanazawa M, Kobayashi M. Source: Pediatric Neurology. 1999 January; 20(1): 31-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10029257&dopt=Abstract

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Immune responses to dystropin: implications for gene therapy of Duchenne muscular dystrophy. Author(s): Ferrer A, Wells KE, Wells DJ. Source: Gene Therapy. 2000 September; 7(17): 1439-46. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11001363&dopt=Abstract

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Immunocytochemical analysis of human muscular dystrophy. Author(s): Sewry CA. Source: Microscopy Research and Technique. 2000 February 1-15; 48(3-4): 142-54. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10679962&dopt=Abstract

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Immunocytochemistry of nuclear domains and Emery-Dreifuss muscular dystrophy pathophysiology. Author(s): Maraldi NM, Lattanzi G, Sabatelli P, Ognibene A, Columbaro M, Capanni C, Rutigliano C, Mattioli E, Squarzoni S. Source: Eur J Histochem. 2003; 47(1): 3-16. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12685553&dopt=Abstract

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Immunohistochemical alterations of dystrophin in congenital muscular dystrophy. Author(s): Werneck LC, Bonilla E. Source: Arquivos De Neuro-Psiquiatria. 1995 September; 53(3-A): 416-23. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8540815&dopt=Abstract


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Immunohistochemical staining of dystrophin on formalin-fixed paraffin-embedded sections in Duchenne/Becker muscular dystrophy and manifesting carriers of Duchenne muscular dystrophy. Author(s): Hoshino S, Ohkoshi N, Watanabe M, Shoji S. Source: Neuromuscular Disorders : Nmd. 2000 August; 10(6): 425-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10899449&dopt=Abstract

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Immunohistochemical study of merosin-negative congenital muscular dystrophy: laminin alpha 2 deficiency in skin biopsy. Author(s): Marbini A, Bellanova MF, Ferrari A, Lodesani M, Gemignani F. Source: Acta Neuropathologica. 1997 August; 94(2): 103-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9255383&dopt=Abstract

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Impact of carrier status determination for Duchenne/Becker muscular dystrophy by computer-assisted laser densitometry. Author(s): Allingham-Hawkins DJ, McGlynn-Steele LK, Brown CA, Sutherland J, Ray PN. Source: American Journal of Medical Genetics. 1998 January 13; 75(2): 171-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9450879&dopt=Abstract

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Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Author(s): Simonds AK, Muntoni F, Heather S, Fielding S. Source: Thorax. 1998 November; 53(11): 949-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10193393&dopt=Abstract

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Impact of pregnancy on respiratory capacity in women with muscular dystrophy and kyphoscoliosis. A case report. Author(s): Gamzu R, Shenhav M, Fainaru O, Almog B, Kupferminc M, Lessing JB. Source: J Reprod Med. 2002 January; 47(1): 53-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11838313&dopt=Abstract

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Impairment of cardiac autonomic function in patients with Duchenne muscular dystrophy: relationship to myocardial and respiratory function. Author(s): Lanza GA, Dello Russo A, Giglio V, De Luca L, Messano L, Santini C, Ricci E, Damiani A, Fumagalli G, De Martino G, Mangiola F, Bellocci F. Source: American Heart Journal. 2001 May; 141(5): 808-12. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11320370&dopt=Abstract

Studies 171

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Impairment of caveolae formation and T-system disorganization in human muscular dystrophy with caveolin-3 deficiency. Author(s): Minetti C, Bado M, Broda P, Sotgia F, Bruno C, Galbiati F, Volonte D, Lucania G, Pavan A, Bonilla E, Lisanti MP, Cordone G. Source: American Journal of Pathology. 2002 January; 160(1): 265-70. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11786420&dopt=Abstract

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Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD. Author(s): Upadhyaya M, Maynard J, Rogers MT, Lunt PW, Jardine P, Ravine D, Harper PS. Source: Journal of Medical Genetics. 1997 June; 34(6): 476-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9192267&dopt=Abstract

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In situ measurements of muscle fiber conduction velocity in Duchenne muscular dystrophy. Author(s): Al-Ani FS, Hamdan FB, Shaikhly KI. Source: Saudi Med J. 2001 March; 22(3): 259-61. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11307114&dopt=Abstract

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In utero fetal muscle biopsy alters diagnosis and carrier risks in Duchenne and Becker muscular dystrophy. Author(s): Evans MI, Krivchenia EL, Johnson MP, Quintero RA, King M, Pegoraro E, Hoffman EP. Source: Fetal Diagnosis and Therapy. 1995 March-April; 10(2): 71-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7794517&dopt=Abstract

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In utero fetal muscle biopsy in the diagnosis of Duchenne muscular dystrophy. Author(s): Ladwig D, Mowat D, Tobias V, Taylor PJ, Buckley MF, McNally G, Challis D. Source: The Australian & New Zealand Journal of Obstetrics & Gynaecology. 2002 February; 42(1): 79-82. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11926646&dopt=Abstract

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In utero fetal muscle biopsy: a precious aid for the prenatal diagnosis of Duchenne muscular dystrophy. Author(s): Heckel S, Favre R, Flori J, Koenig M, Mandel J, Gasser B, Chaigne D. Source: Fetal Diagnosis and Therapy. 1999 May-June; 14(3): 127-32. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10364661&dopt=Abstract

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Incidence of cerebral infarction in Duchenne muscular dystrophy. Author(s): Hanajima R, Kawai M. Source: Muscle & Nerve. 1996 July; 19(7): 928. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8965857&dopt=Abstract


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Increase in fetal breech presentation in female carriers of Duchenne muscular dystrophy. Author(s): Geifman-Holtzman O, Bernstein IM, Capeless EL, Hawley P, Specht LA, Bianchi DW. Source: American Journal of Medical Genetics. 1997 December 19; 73(3): 276-8. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9415684&dopt=Abstract

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Increased cerebral choline-compounds in Duchenne muscular dystrophy. Author(s): Kato T, Nishina M, Matsushita K, Hori E, Akaboshi S, Takashima S. Source: Neuroreport. 1997 April 14; 8(6): 1435-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9172149&dopt=Abstract

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Increased expression of IGF-binding protein-5 in Duchenne muscular dystrophy (DMD) fibroblasts correlates with the fibroblast-induced downregulation of DMD myoblast growth: an in vitro analysis. Author(s): Melone MA, Peluso G, Galderisi U, Petillo O, Cotrufo R. Source: Journal of Cellular Physiology. 2000 October; 185(1): 143-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10942528&dopt=Abstract

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Increased levels of leukemia inhibitory factor mRNA in muscular dystrophy and human muscle trauma. Author(s): Reardon KA, Kapsa RM, Davis J, Kornberg AJ, Austin L, Choong P, Byrne E. Source: Muscle & Nerve. 2000 June; 23(6): 962-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10842275&dopt=Abstract

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Increased number of caveolae and caveolin-3 overexpression in Duchenne muscular dystrophy. Author(s): Repetto S, Bado M, Broda P, Lucania G, Masetti E, Sotgia F, Carbone I, Pavan A, Bonilla E, Cordone G, Lisanti MP, Minetti C. Source: Biochemical and Biophysical Research Communications. 1999 August 11; 261(3): 547-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10441463&dopt=Abstract

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Increased solubility of lamins and redistribution of lamin C in X-linked EmeryDreifuss muscular dystrophy fibroblasts. Author(s): Markiewicz E, Venables R, Mauricio-Alvarez-Reyes, Quinlan R, Dorobek M, Hausmanowa-Petrucewicz I, Hutchison C. Source: Journal of Structural Biology. 2002 October-December; 140(1-3): 241-53. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12490172&dopt=Abstract

Studies 173

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Indications for a novel muscular dystrophy pathway. gamma-filamin, the musclespecific filamin isoform, interacts with myotilin. Author(s): van der Ven PF, Wiesner S, Salmikangas P, Auerbach D, Himmel M, Kempa S, Hayess K, Pacholsky D, Taivainen A, Schroder R, Carpen O, Furst DO. Source: The Journal of Cell Biology. 2000 October 16; 151(2): 235-48. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11038172&dopt=Abstract

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Indicators of need for mechanical ventilation in Duchenne muscular dystrophy and spinal muscular atrophy. Author(s): Lyager S, Steffensen B, Juhl B. Source: Chest. 1995 September; 108(3): 779-85. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7656633&dopt=Abstract

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Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Author(s): Arahata K, Ishihara T, Fukunaga H, Orimo S, Lee JH, Goto K, Nonaka I. Source: Muscle & Nerve. 1995; 2: S56-66. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7739627&dopt=Abstract

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Infraspinatus muscle hypertrophy and wasting of axillary folds as the important signs in Duchenne muscular dystrophy. Author(s): Pradhan S, Mittal B. Source: Clinical Neurology and Neurosurgery. 1995 May; 97(2): 134-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7656486&dopt=Abstract

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Inhalation anesthetics and Duchenne's muscular dystrophy. Author(s): Goresky GV, Cox RG. Source: Canadian Journal of Anaesthesia = Journal Canadien D'anesthesie. 1999 June; 46(6): 525-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10391598&dopt=Abstract

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Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeral muscular dystrophy. Author(s): Vitelli F, Villanova M, Malandrini A, Bruttini M, Piccini M, Merlini L, Guazzi G, Renieri A. Source: Muscle & Nerve. 1999 October; 22(10): 1437-41. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10487912&dopt=Abstract

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Inspiratory flow reserve in boys with Duchenne muscular dystrophy. Author(s): De Bruin PF, Ueki J, Bush A, Y Manzur A, Watson A, Pride NB. Source: Pediatric Pulmonology. 2001 June; 31(6): 451-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11389578&dopt=Abstract


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Insulin-like growth factor-I and high protein diet decrease calpain-mediated proteolysis in murine muscular dystrophy. Author(s): Wingertzahn MA, Zdanowicz MM, Slonim AE. Source: Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.). 1998 July; 218(3): 244-50. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9648944&dopt=Abstract

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Integrin alpha 7 beta 1 in muscular dystrophy/myopathy of unknown etiology. Author(s): Pegoraro E, Cepollaro F, Prandini P, Marin A, Fanin M, Trevisan CP, ElMesslemani AH, Tarone G, Engvall E, Hoffman EP, Angelini C. Source: American Journal of Pathology. 2002 June; 160(6): 2135-43. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12057917&dopt=Abstract

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Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy. Author(s): Vachon PH, Xu H, Liu L, Loechel F, Hayashi Y, Arahata K, Reed JC, Wewer UM, Engvall E. Source: The Journal of Clinical Investigation. 1997 October 1; 100(7): 1870-81. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9312189&dopt=Abstract

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Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients. Author(s): Cotton S, Voudouris NJ, Greenwood KM. Source: Developmental Medicine and Child Neurology. 2001 July; 43(7): 497-501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11463183&dopt=Abstract

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Inter- and intrachromosomal sub-telomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis. Author(s): Lemmers RJ, van der Maarel SM, van Deutekom JC, van der Wielen MJ, Deidda G, Dauwerse HG, Hewitt J, Hofker M, Bakker E, Padberg GW, Frants RR. Source: Human Molecular Genetics. 1998 August; 7(8): 1207-14. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9668160&dopt=Abstract

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Intestinal pseudoobstruction as a feature of myotonic muscular dystrophy. Author(s): Fuger K, Barnert J, Hopfner W, Wienbeck M. Source: Zeitschrift Fur Gastroenterologie. 1995 September; 33(9): 534-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8525657&dopt=Abstract

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Intraarterial atracurium followed by difficult intubation in a child with congenital muscular dystrophy. Author(s): Gorman A, Dearlove OR. Source: Paediatric Anaesthesia. 1999; 9(3): 277. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10320613&dopt=Abstract

Studies 175

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Intracellular trafficking of emerin, the Emery-Dreifuss muscular dystrophy protein. Author(s): Ostlund C, Ellenberg J, Hallberg E, Lippincott-Schwartz J, Worman HJ. Source: Journal of Cell Science. 1999 June; 112 ( Pt 11): 1709-19. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10318763&dopt=Abstract

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Intrafamilial phenotypic variation in limb-girdle muscular dystrophy type 2C with compound heterozygous mutations. Author(s): Takano A, Bonnemann CG, Honda H, Sakai M, Feener CA, Kunkel LM, Sobue G. Source: Muscle & Nerve. 2000 May; 23(5): 807-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10797406&dopt=Abstract

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Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews. Author(s): Blumen SC, Sadeh M, Korczyn AD, Rouche A, Nisipeanu P, Asherov A, Tome FM. Source: Neurology. 1996 May; 46(5): 1324-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8628475&dopt=Abstract

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Intranuclear inclusions in oculopharyngeal muscular dystrophy contain poly(A) binding protein 2. Author(s): Becher MW, Kotzuk JA, Davis LE, Bear DG. Source: Annals of Neurology. 2000 November; 48(5): 812-5. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11079550&dopt=Abstract

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Introduction to muscular dystrophy. Author(s): Porter JD. Source: Microscopy Research and Technique. 2000 February 1-15; 48(3-4): 127-30. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10679960&dopt=Abstract

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Is dystrophin always altered in Becker muscular dystrophy patients? Author(s): Vainzof M, Passos-Bueno MR, Pavanello RC, Zatz M. Source: Journal of the Neurological Sciences. 1995 July; 131(1): 99-104. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7561956&dopt=Abstract

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Is glutamine a 'conditionally essential' amino acid in Duchenne muscular dystrophy? Author(s): Hankard R, Mauras N, Hammond D, Haymond M, Darmaun D. Source: Clinical Nutrition (Edinburgh, Lothian). 1999 December; 18(6): 365-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10634922&dopt=Abstract


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Is there selection in favour of heterozygotes in families with merosin-deficient congenital muscular dystrophy? Author(s): D'Alessandro M, Naom I, Ferlini A, Sewry C, Dubowitz V, Muntoni F. Source: Human Genetics. 1999 October; 105(4): 308-13. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10543397&dopt=Abstract

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It is bundle branch reentry linked to any kind of muscular dystrophy? Author(s): Merino JL, Peinado R. Source: Journal of Cardiovascular Electrophysiology. 1998 December; 9(12): 1397-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9869540&dopt=Abstract

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Juvenile limb-girdle muscular dystrophy. Clinical, histopathological and genetic data from a small community living in the Reunion Island. Author(s): Fardeau M, Hillaire D, Mignard C, Feingold N, Feingold J, Mignard D, de Ubeda B, Collin H, Tome FM, Richard I, Beckmann J. Source: Brain; a Journal of Neurology. 1996 February; 119 ( Pt 1): 295-308. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8624690&dopt=Abstract

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Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy. Author(s): van der Kooi AJ, Bonne G, Eymard B, Duboc D, Talim B, Van der Valk M, Reiss P, Richard P, Demay L, Merlini L, Schwartz K, Busch HF, de Visser M. Source: Neurology. 2002 August 27; 59(4): 620-3. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12196663&dopt=Abstract

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Laminin abnormality in severe childhood autosomal recessive muscular dystrophy. Author(s): Yamada H, Tome FM, Higuchi I, Kawai H, Azibi K, Chaouch M, Roberds SL, Tanaka T, Fujita S, Mitsui T, et al. Source: Laboratory Investigation; a Journal of Technical Methods and Pathology. 1995 June; 72(6): 715-22. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7783429&dopt=Abstract

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Laminin alpha 2-chain gene mutations in two siblings presenting with limb-girdle muscular dystrophy. Author(s): Naom I, D'Alessandro M, Sewry CA, Philpot J, Manzur AY, Dubowitz V, Muntoni F. Source: Neuromuscular Disorders : Nmd. 1998 October; 8(7): 495-501. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9829280&dopt=Abstract

Studies 177

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Laminin alpha2 chain-deficient congenital muscular dystrophy: variable epitope expression in severe and mild cases. Author(s): Cohn RD, Herrmann R, Sorokin L, Wewer UM, Voit T. Source: Neurology. 1998 July; 51(1): 94-100. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9674785&dopt=Abstract

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Laminin alpha2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice. Author(s): Guo LT, Zhang XU, Kuang W, Xu H, Liu LA, Vilquin JT, Miyagoe-Suzuki Y, Takeda S, Ruegg MA, Wewer UM, Engvall E. Source: Neuromuscular Disorders : Nmd. 2003 March; 13(3): 207-15. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12609502&dopt=Abstract

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Laminin alpha2 deficient congenital muscular dystrophy: prenatal diagnosis. Author(s): Nass D, Goldberg I, Sadeh M. Source: Early Human Development. 1999 May; 55(1): 19-24. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10367979&dopt=Abstract

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Laminin alpha2 muscular dystrophy: genotype/phenotype studies of 22 patients. Author(s): Pegoraro E, Marks H, Garcia CA, Crawford T, Mancias P, Connolly AM, Fanin M, Martinello F, Trevisan CP, Angelini C, Stella A, Scavina M, Munk RL, Servidei S, Bonnemann CC, Bertorini T, Acsadi G, Thompson CE, Gagnon D, Hoganson G, Carver V, Zimmerman RA, Hoffman EP. Source: Neurology. 1998 July; 51(1): 101-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9674786&dopt=Abstract

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Late onset and very mild course of Xp21 Becker type muscular dystrophy. Author(s): Bosone I, Bortolotto S, Mongini T, Doriguzzi C, Chiado-Piat L, Ugo I, Mutani R, Palmucci L. Source: Clin Neuropathol. 2001 September-October; 20(5): 196-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11594504&dopt=Abstract

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Late onset foot-drop muscular dystrophy with rimmed vacuoles. Author(s): Partanen J, Laulumaa V, Paljarvi L, Partanen K, Naukkarinen A. Source: Journal of the Neurological Sciences. 1994 September; 125(2): 158-67. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7807161&dopt=Abstract

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Late onset muscular dystrophy proximal myopathy and recurrent falls in the elderly. Author(s): Boonen S. Source: Clinical Rheumatology. 1995 September; 14(5): 586-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8549104&dopt=Abstract


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Late onset muscular dystrophy with cerebral white matter changes due to partial merosin deficiency. Author(s): Tan E, Topaloglu H, Sewry C, Zorlu Y, Naom I, Erdem S, D'Alessandro M, Muntoni F, Dubowitz V. Source: Neuromuscular Disorders : Nmd. 1997 March; 7(2): 85-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9131648&dopt=Abstract

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Learning and transfer in two perceptual-motor skills in Duchenne muscular dystrophy. Author(s): Nakafuji A, Tsuji K. Source: Percept Mot Skills. 2001 October; 93(2): 339-52. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11769887&dopt=Abstract

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Left ventricular function and perfusion in Becker's muscular dystrophy. Author(s): Mansi L, Pace L, Politano L, Rambaldi PF, Di Gregorio F, Raia P, Petretta VR, Nigro G. Source: Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine. 1997 April; 38(4): 563-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9098202&dopt=Abstract

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Left ventricular non-compaction in a patient with becker's muscular dystrophy. Author(s): Stollberger C, Finsterer J, Blazek G, Bittner RE. Source: Heart (British Cardiac Society). 1996 October; 76(4): 380. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8983693&dopt=Abstract

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Lesson of the week: late diagnosis of Duchenne's muscular dystrophy presenting as global developmental delay. Author(s): Essex C, Roper H. Source: Bmj (Clinical Research Ed.). 2001 July 7; 323(7303): 37-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11440945&dopt=Abstract

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Lethal congenital muscular dystrophy in two sibs with arthrogryposis multiplex: new entity or variant of cobblestone lissencephaly syndrome? Author(s): Seidahmed MZ, Sunada Y, Ozo CO, Hamid F, Campbell KP, Salih MA. Source: Neuropediatrics. 1996 December; 27(6): 305-10. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9050048&dopt=Abstract

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Lightweight, modular knee-ankle-foot orthosis for Duchenne muscular dystrophy: design, development, and evaluation. Author(s): Taktak DM, Bowker P. Source: Archives of Physical Medicine and Rehabilitation. 1995 December; 76(12): 115662. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8540794&dopt=Abstract

Studies 179

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Limb girdle muscular dystrophy in Manitoba Hutterites does not map to any of the known LGMD loci. Author(s): Weiler T, Greenberg CR, Nylen E, Morgan K, Fujiwara TM, Crumley MJ, Zelinski T, Halliday W, Nickel B, Triggs-Raine B, Wrogemann K. Source: American Journal of Medical Genetics. 1997 October 31; 72(3): 363-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9332671&dopt=Abstract

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Limb girdle muscular dystrophy type 2A (CAPN3): mapping using allelic association. Author(s): Lonjou C, Collins A, Beckmann J, Allamand V, Morton N. Source: Human Heredity. 1998 November-December; 48(6): 333-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9813455&dopt=Abstract

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Limb girdle muscular dystrophy type 2A presenting with cardiac arrest. Author(s): Dirik E, Aydin A, Kurul S, Sahin B. Source: Pediatric Neurology. 2001 March; 24(3): 235-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11301229&dopt=Abstract

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Limb girdle muscular dystrophy: a pathological and immunohistochemical reevaluation. Author(s): van der Kooi AJ, Ginjaar HB, Busch HF, Wokke JH, Barth PG, de Visser M. Source: Muscle & Nerve. 1998 May; 21(5): 584-90. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9572237&dopt=Abstract

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Limb girdle muscular dystrophy: a prospective follow-up study of functional impairment. Author(s): Stubgen JP, Stipp A. Source: Muscle & Nerve. 1997 April; 20(4): 453-60. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9121503&dopt=Abstract

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Limb girdle muscular dystrophy: a quantitative electromyographic study. Author(s): Stubgen JP. Source: Electromyogr Clin Neurophysiol. 1995 October; 35(6): 351-7. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8785932&dopt=Abstract

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Limb girdle muscular dystrophy: a radiologic and manometric study of the pharynx and esophagus. Author(s): Stubgen JP. Source: Dysphagia. 1996 Winter; 11(1): 25-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8556875&dopt=Abstract


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Limb girdle muscular dystrophy: description of a phenotype. Author(s): Stubgen JP. Source: Muscle & Nerve. 1994 December; 17(12): 1449-55. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7969245&dopt=Abstract

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Limb girdle muscular dystrophy: weakness and disease duration as predictors of functional impairment. Author(s): Stubgen JP, Lahouter A. Source: Muscle & Nerve. 1994 August; 17(8): 873-80. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8041394&dopt=Abstract

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Limb-girdle muscular dystrophy 2C: clinical aspects. Author(s): Ben Hamida M, Ben Hamida C, Zouari M, Belal S, Hentati F. Source: Neuromuscular Disorders : Nmd. 1996 December; 6(6): 493-4. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9027861&dopt=Abstract

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Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype. Author(s): Weiler T, Greenberg CR, Nylen E, Halliday W, Morgan K, Eggertson D, Wrogemann K. Source: American Journal of Human Genetics. 1996 October; 59(4): 872-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8808603&dopt=Abstract

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Limb-girdle muscular dystrophy in Guipuzcoa (Basque Country, Spain). Author(s): Urtasun M, Saenz A, Roudaut C, Poza JJ, Urtizberea JA, Cobo AM, Richard I, Garcia Bragado F, Leturcq F, Kaplan JC, Marti Masso JF, Beckmann JS, Lopez de Munain A. Source: Brain; a Journal of Neurology. 1998 September; 121 ( Pt 9): 1735-47. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9762961&dopt=Abstract

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Limb-girdle muscular dystrophy or spinal muscular atrophy: a source of diagnostic confusion? Author(s): Pogue R, Jackson T, Sayli B, Curtis A, Bushby KM. Source: Journal of Medical Genetics. 1997 November; 34(11): 958-9. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9391899&dopt=Abstract

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Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Author(s): Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE. Source: Nature Genetics. 2000 February; 24(2): 163-6. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10655062&dopt=Abstract

Studies 181

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Limb-girdle muscular dystrophy type 2H associated with mutation in TRIM32, a putative E3-ubiquitin-ligase gene. Author(s): Frosk P, Weiler T, Nylen E, Sudha T, Greenberg CR, Morgan K, Fujiwara TM, Wrogemann K. Source: American Journal of Human Genetics. 2002 March; 70(3): 663-72. Epub 2002 January 29. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11822024&dopt=Abstract

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Limb-girdle muscular dystrophy with apparently different clinical courses within sexes in a large inbred kindred. Author(s): Leal GF, da-Silva EO. Source: Journal of Medical Genetics. 1999 September; 36(9): 714-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=10507732&dopt=Abstract

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Limb-girdle muscular dystrophy. Author(s): Mathews KD, Moore SA. Source: Curr Neurol Neurosci Rep. 2003 January; 3(1): 78-85. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=12507416&dopt=Abstract

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Limb-girdle muscular dystrophy: a follow-up study of 79 patients. Author(s): Mahjneh I, Bushby K, Pizzi A, Bashir R, Marconi G. Source: Acta Neurologica Scandinavica. 1996 September; 94(3): 177-89. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8899051&dopt=Abstract

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Limb-girdle muscular dystrophy: clinical and pathologic reevaluation. Author(s): Yamanouchi Y, Arikawa E, Arahata K, Ozawa E, Nonaka I. Source: Journal of the Neurological Sciences. 1995 March; 129(1): 15-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7751838&dopt=Abstract

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Limb-girdle muscular dystrophy: one gene with different phenotypes, one phenotype with different genes. Author(s): Zatz M, Vainzof M, Passos-Bueno MR. Source: Current Opinion in Neurology. 2000 October; 13(5): 511-7. Review. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=11073356&dopt=Abstract

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Limitation of eye movement in merosin-deficient congenital muscular dystrophy. Author(s): Philpot J, Muntoni F. Source: Lancet. 1999 January 23; 353(9149): 297-8. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9929033&dopt=Abstract


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Linkage analyses in tibial muscular dystrophy. Author(s): Nokelainen P, Udd B, Somer H, Peltonen L. Source: Human Heredity. 1996 March-April; 46(2): 98-107. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8666419&dopt=Abstract

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Linkage analysis in autosomal recessive limb-girdle muscular dystrophy (AR LGMD) maps a sixth form to 5q33-34 (LGMD2F) and indicates that there is at least one more subtype of AR LGMD. Author(s): Passos-Bueno MR, Moreira ES, Vainzof M, Marie SK, Zatz M. Source: Human Molecular Genetics. 1996 June; 5(6): 815-20. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=8776597&dopt=Abstract

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Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Author(s): Messina DN, Speer MC, Pericak-Vance MA, McNally EM. Source: American Journal of Human Genetics. 1997 October; 61(4): 909-17. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=9382102&dopt=Abstract

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Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14. Author(s): Bejaoui K, Hirabayashi K, Hentati F, Haines JL, Ben Hamida C, Belal S, Miller RG, McKenna-Yasek D, Weissenbach J, Rowland LP, et al. Source: Neurology. 1995 April; 45(4): 768-72. http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_ uids=7723968&dopt=Abstract

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Linkage-disequilibrium mapping narrows the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region to

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