Nonsyndromic Deafness - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

NONSYNDROMIC DEAFNESS A 3-in-1 Medical Reference A Bibliography and Dictionary for Physicians, Patients, and Genome...

Author: Philip M. Parker

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NONSYNDROMIC DEAFNESS

A

3-in-1

Medical

Reference

A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES

NONSYNDROMIC DEAFNESS A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS

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. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 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., 1960Nonsyndromic Deafness: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11381-3 1. Nonsyndromic Deafness-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 nonsyndromic deafness. 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 Chaired Professor of Management Science 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. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health

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Table of Contents CHAPTER 1. INTRODUCTION ............................................................................................................. 1 CHAPTER 2. STUDIES ON NONSYNDROMIC DEAFNESS .................................................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Nonsyndromic Deafness?................................................................................................. 3 How Common Is Nonsyndromic Deafness? .................................................................................. 4 What Are the Genetic Changes Related to Nonsyndromic Deafness?........................................... 4 How Do People Inherit Nonsyndromic Deafness? ........................................................................ 6 Where Can I Find Additional Information about Nonsyndromic Deafness? ................................ 6 References....................................................................................................................................... 9 What Is Mitochondrial DNA?..................................................................................................... 10 What Conditions Are Related to Mitochondrial DNA? .............................................................. 11 Is There a Standard Way to Diagram Mitochondrial DNA? ...................................................... 13 References..................................................................................................................................... 13 What Is the Official Name of the ACTG1 Gene? ......................................................................... 14 What Is the Normal Function of the ACTG1 Gene? ................................................................... 14 What Conditions Are Related to the ACTG1 Gene? ................................................................... 15 Where Is the ACTG1 Gene Located? ........................................................................................... 15 References..................................................................................................................................... 15 What Is the Official Name of the CDH23 Gene? ......................................................................... 16 What Is the Normal Function of the CDH23 Gene? ................................................................... 16 What Conditions Are Related to the CDH23 Gene? ................................................................... 16 Where Is the CDH23 Gene Located? ........................................................................................... 17 References..................................................................................................................................... 17 What Is the Official Name of the CLDN14 Gene?....................................................................... 19 What Is the Normal Function of the CLDN14 Gene? ................................................................. 19 What Conditions Are Related to the CLDN14 Gene? ................................................................. 19 Where Is the CLDN14 Gene Located? ......................................................................................... 19 References..................................................................................................................................... 20 What Is the Official Name of the COCH Gene? .......................................................................... 20 What Is the Normal Function of the COCH Gene?..................................................................... 21 What Conditions Are Related to the COCH Gene?..................................................................... 21 Where Is the COCH Gene Located?............................................................................................. 21 References..................................................................................................................................... 22 What Is the Official Name of the COL11A2 Gene? ..................................................................... 23 What Is the Normal Function of the COL11A2 Gene? ............................................................... 23 What Conditions Are Related to the COL11A2 Gene? ............................................................... 24 Where Is the COL11A2 Gene Located? ....................................................................................... 25 References..................................................................................................................................... 25 What Is the Official Name of the DFNA5 Gene?......................................................................... 27 What Is the Normal Function of the DFNA5 Gene? ................................................................... 27 What Conditions Are Related to the DFNA5 Gene? ................................................................... 27 Where Is the DFNA5 Gene Located?........................................................................................... 27 References..................................................................................................................................... 28 What Is the Official Name of the DFNB31 Gene? ....................................................................... 28 What Is the Normal Function of the DFNB31 Gene? ................................................................. 28 What Conditions Are Related to the DFNB31 Gene? ................................................................. 29 Where Is the DFNB31 Gene Located? ......................................................................................... 29 References..................................................................................................................................... 30 What Is the Official Name of the DFNB59 Gene? ....................................................................... 30 What Is the Normal Function of the DFNB59 Gene? ................................................................. 30

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What Conditions Are Related to the DFNB59 Gene? ................................................................. 31 Where Is the DFNB59 Gene Located? ......................................................................................... 31 References..................................................................................................................................... 31 What Is the Official Name of the ESPN Gene?............................................................................ 32 What Is the Normal Function of the ESPN Gene? ...................................................................... 32 What Conditions Are Related to the ESPN Gene? ...................................................................... 32 Where Is the ESPN Gene Located? .............................................................................................. 32 References..................................................................................................................................... 33 What Is the Official Name of the EYA4 Gene?............................................................................ 33 What Is the Normal Function of the EYA4 Gene? ...................................................................... 34 What Conditions Are Related to the EYA4 Gene? ...................................................................... 34 Where Is the EYA4 Gene Located? .............................................................................................. 34 References..................................................................................................................................... 35 What Is the Official Name of the GJB2 Gene? ............................................................................. 35 What Is the Normal Function of the GJB2 Gene?........................................................................ 36 What Conditions Are Related to the GJB2 Gene?........................................................................ 36 Where Is the GJB2 Gene Located?................................................................................................ 37 References..................................................................................................................................... 37 What Is the Official Name of the GJB6 Gene? ............................................................................. 38 What Is the Normal Function of the GJB6 Gene?........................................................................ 38 What Conditions Are Related to the GJB6 Gene?........................................................................ 38 Where Is the GJB6 Gene Located?................................................................................................ 39 References..................................................................................................................................... 39 What Is the Official Name of the KCNQ4 Gene? ........................................................................ 40 What Is the Normal Function of the KCNQ4 Gene?................................................................... 40 What Conditions Are Related to the KCNQ4 Gene?................................................................... 41 Where Is the KCNQ4 Gene Located?........................................................................................... 41 References..................................................................................................................................... 42 What Is the Official Name of the LHFPL5 Gene?........................................................................ 42 What Is the Normal Function of the LHFPL5 Gene? .................................................................. 42 What Conditions Are Related to the LHFPL5 Gene? .................................................................. 43 Where Is the LHFPL5 Gene Located? .......................................................................................... 43 References..................................................................................................................................... 43 What Is the Official Name of the MT-TS1 Gene?........................................................................ 44 What Is the Normal Function of the MT-TS1 Gene? .................................................................. 44 What Conditions Are Related to the MT-TS1 Gene? .................................................................. 44 Where Is the MT-TS1 Gene Located? .......................................................................................... 45 References..................................................................................................................................... 45 What Is the Official Name of the MYO15A Gene? ..................................................................... 46 What Is the Normal Function of the MYO15A Gene?................................................................ 46 What Conditions Are Related to the MYO15A Gene?................................................................ 47 Where Is the MYO15A Gene Located?........................................................................................ 47 References..................................................................................................................................... 47 What Is the Official Name of the MYO6 Gene? .......................................................................... 48 What Is the Normal Function of the MYO6 Gene?..................................................................... 48 What Conditions Are Related to the MYO6 Gene?..................................................................... 49 Where Is the MYO6 Gene Located?............................................................................................. 49 References..................................................................................................................................... 49 What Is the Official Name of the MYO7A Gene? ....................................................................... 50 What Is the Normal Function of the MYO7A Gene?.................................................................. 50 What Conditions Are Related to the MYO7A Gene?.................................................................. 51 Where Is the MYO7A Gene Located?.......................................................................................... 51 References..................................................................................................................................... 52 What Is the Official Name of the OTOF Gene? ........................................................................... 53

Contents

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What Is the Normal Function of the OTOF Gene? ..................................................................... 53 What Conditions Are Related to the OTOF Gene? ..................................................................... 53 Where Is the OTOF Gene Located? ............................................................................................. 54 References..................................................................................................................................... 54 What Is the Official Name of the PCDH15 Gene?....................................................................... 55 What Is the Normal Function of the PCDH15 Gene? ................................................................. 55 What Conditions Are Related to the PCDH15 Gene? ................................................................. 56 Where Is the PCDH15 Gene Located?......................................................................................... 56 References..................................................................................................................................... 56 What Is the Official Name of the POU3F4 Gene? ....................................................................... 58 What Is the Normal Function of the POU3F4 Gene? ................................................................. 58 What Conditions Are Related to the POU3F4 Gene? ................................................................. 58 Where Is the POU3F4 Gene Located? ......................................................................................... 58 References..................................................................................................................................... 59 What Is the Official Name of the SLC26A4 Gene?...................................................................... 60 What Is the Normal Function of the SLC26A4 Gene? ................................................................ 60 What Conditions Are Related to the SLC26A4 Gene? ................................................................ 60 Where Is the SLC26A4 Gene Located? ........................................................................................ 61 References..................................................................................................................................... 61 What Is the Official Name of the STRC Gene?............................................................................ 62 What Is the Normal Function of the STRC Gene? ...................................................................... 62 What Conditions Are Related to the STRC Gene? ...................................................................... 62 Where Is the STRC Gene Located? .............................................................................................. 63 References..................................................................................................................................... 63 What Is the Official Name of the TECTA Gene? ......................................................................... 63 What Is the Normal Function of the TECTA Gene? ................................................................... 64 What Conditions Are Related to the TECTA Gene? ................................................................... 64 Where Is the TECTA Gene Located? ........................................................................................... 64 References..................................................................................................................................... 65 What Is the Official Name of the TMC1 Gene? ........................................................................... 65 What Is the Normal Function of the TMC1 Gene? ..................................................................... 65 What Conditions Are Related to the TMC1 Gene? ..................................................................... 66 Where Is the TMC1 Gene Located? ............................................................................................. 66 References..................................................................................................................................... 66 What Is the Official Name of the TMIE Gene?............................................................................ 67 What Is the Normal Function of the TMIE Gene? ...................................................................... 67 What Conditions Are Related to the TMIE Gene? ...................................................................... 67 Where Is the TMIE Gene Located? .............................................................................................. 68 References..................................................................................................................................... 68 What Is the Official Name of the TMPRSS3 Gene? .................................................................... 68 What Is the Normal Function of the TMPRSS3 Gene?............................................................... 69 What Conditions Are Related to the TMPRSS3 Gene?............................................................... 69 Where Is the TMPRSS3 Gene Located?....................................................................................... 69 References..................................................................................................................................... 70 What Is the Official Name of the TRIOBP Gene? ....................................................................... 71 What Is the Normal Function of the TRIOBP Gene?.................................................................. 71 What Conditions Are Related to the TRIOBP Gene?.................................................................. 72 Where Is the TRIOBP Gene Located?.......................................................................................... 72 References..................................................................................................................................... 72 What Is the Official Name of the USH1C Gene?......................................................................... 73 What Is the Normal Function of the USH1C Gene? ................................................................... 73 What Conditions Are Related to the USH1C Gene? ................................................................... 73 Where Is the USH1C Gene Located? ........................................................................................... 74 References..................................................................................................................................... 74

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Contents What Is the Official Name of the WFS1 Gene?............................................................................ 75 What Is the Normal Function of the WFS1 Gene? ...................................................................... 76 What Conditions Are Related to the WFS1 Gene? ...................................................................... 76 Where Is the WFS1 Gene Located? .............................................................................................. 77 References..................................................................................................................................... 77 What Is the Official Name of the MT-RNR1 Gene?.................................................................... 78 What Is the Normal Function of the MT-RNR1 Gene? .............................................................. 78 What Conditions Are Related to the MT-RNR1 Gene? .............................................................. 78 Where Is the MT-RNR1 Gene Located? ...................................................................................... 79 References..................................................................................................................................... 79 What Is the Official Name of the ATP2B2 Gene?........................................................................ 80 What Is the Normal Function of the ATP2B2 Gene? .................................................................. 80 What Conditions Are Related to the ATP2B2 Gene? .................................................................. 81 Where Is the ATP2B2 Gene Located? .......................................................................................... 81 References..................................................................................................................................... 81 What Is the Official Name of the GJB3 Gene? ............................................................................. 82 What Is the Normal Function of the GJB3 Gene?........................................................................ 82 What Conditions Are Related to the GJB3 Gene?........................................................................ 82 Where Is the GJB3 Gene Located?................................................................................................ 83 References..................................................................................................................................... 83 What Is the Official Name of the MYO1A Gene? ....................................................................... 84 What Is the Normal Function of the MYO1A Gene?.................................................................. 84 What Conditions Are Related to the MYO1A Gene?.................................................................. 84 Where Is the MYO1A Gene Located?.......................................................................................... 85 References..................................................................................................................................... 85 Federally Funded Research on Nonsyndromic Deafness ............................................................. 86 The National Library of Medicine: PubMed ................................................................................ 91 APPENDIX A. HELP ME UNDERSTAND GENETICS ....................................................................... 109 Overview.................................................................................................................................... 109 The Basics: Genes and How They Work..................................................................................... 109 Genetic Mutations and Health................................................................................................... 120 Inheriting Genetic Conditions ................................................................................................... 126 Genetic Consultation ................................................................................................................. 134 Genetic Testing .......................................................................................................................... 136 Gene Therapy ............................................................................................................................. 142 The Human Genome Project and Genomic Research................................................................. 145 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 148 Overview.................................................................................................................................... 148 NIH Guidelines.......................................................................................................................... 148 NIH Databases........................................................................................................................... 149 Other Commercial Databases..................................................................................................... 152 APPENDIX C. PATIENT RESOURCES .............................................................................................. 153 Overview.................................................................................................................................... 153 Patient Guideline Sources.......................................................................................................... 153 Finding Associations.................................................................................................................. 155 Resources for Patients and Families........................................................................................... 156

ONLINE GLOSSARIES................................................................................................................ 158 Online Dictionary Directories ................................................................................................... 158 NONSYNDROMIC DEAFNESS DICTIONARY..................................................................... 159 INDEX .............................................................................................................................................. 195

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CHAPTER 1. INTRODUCTION 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 nonsyndromic deafness 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 nonsyndromic deafness, 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 nonsyndromic deafness, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of nonsyndromic deafness. 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 nonsyndromic deafness. 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 nonsyndromic deafness, 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.

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.

2

Nonsyndromic Deafness

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. We hope these resources will prove useful to the widest possible audience seeking information on nonsyndromic deafness. The Editors

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CHAPTER 2. STUDIES ON NONSYNDROMIC DEAFNESS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on nonsyndromic deafness. For those interested in basic information about nonsyndromic deafness, we begin with a condition summary published by the National Library of Medicine.

Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on nonsyndromic deafness that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to nonsyndromic deafness is provided.2 The Genetics Home Reference has recently published the following summary for nonsyndromic deafness:

What Is Nonsyndromic Deafness?3 Nonsyndromic deafness is hearing loss that is not associated with other signs and symptoms. In contrast, syndromic deafness involves hearing loss that occurs with abnormalities in other parts of the body. Different types of nonsyndromic deafness are named according to their inheritance patterns. Most forms of nonsyndromic deafness are associated with permanent hearing loss caused by damage to structures in the inner ear. The inner ear consists of three parts: a snail-shaped 2 3

This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness.

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structure called the cochlea that helps process sound, nerves that send information from the cochlea to the brain, and structures involved with balance. Loss of hearing caused by changes in the inner ear is called sensorineural deafness. Hearing loss that results from changes in the middle ear is called conductive hearing loss. The middle ear contains three tiny bones that help transfer sound from the eardrum to the inner ear. Some forms of nonsyndromic deafness, particularly a type of deafness called DFN3, involve changes in both the inner ear and the middle ear. This combination is called mixed hearing loss. The severity of hearing loss varies and can change over time. It can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The loss may be stable, or it may progress as a person gets older. Particular types of nonsyndromic deafness often show distinctive patterns of hearing loss. For example, the loss may be more pronounced at high, middle, or low tones. Nonsyndromic deafness can occur at any age. Hearing loss that is present before a child learns to speak is classified as prelingual or congenital. Hearing loss that occurs after the development of speech is classified as postlingual.

How Common Is Nonsyndromic Deafness? About 1 in 1,000 children in the United States is born with profound deafness, and another 2 to 3 per 1,000 children are born with partial hearing loss. More than half of these cases are caused by genetic factors. Most cases of genetic deafness (70 percent to 80 percent) are nonsyndromic; the remaining cases are caused by specific genetic syndromes. In adults, the chance of developing hearing loss increases with age; hearing loss occurs in half of all people older than 80 years. Overall, 1 in 10 people in the United States—more than 28 million—are currently affected by hearing loss, and this number continues to increase as the population ages.

What Are the Genetic Changes Related to Nonsyndromic Deafness? Nonsyndromic deafness is a condition related to changes in mitochondrial DNA (http://ghr.nlm.nih.gov/chromosome=MT). Mutations in the ACTG1 (http://ghr.nlm.nih.gov/gene=actg1), CDH23 (http://ghr.nlm.nih.gov/gene=cdh23), CLDN14 (http://ghr.nlm.nih.gov/gene=cldn14), COCH (http://ghr.nlm.nih.gov/gene=coch), COL11A2 (http://ghr.nlm.nih.gov/gene=col11a2), DFNA5 (http://ghr.nlm.nih.gov/gene=dfna5), DFNB31 (http://ghr.nlm.nih.gov/gene=dfnb31), DFNB59 (http://ghr.nlm.nih.gov/gene=dfnb59), ESPN (http://ghr.nlm.nih.gov/gene=espn), EYA4 (http://ghr.nlm.nih.gov/gene=eya4), GJB2 (http://ghr.nlm.nih.gov/gene=gjb2), GJB6 (http://ghr.nlm.nih.gov/gene=gjb6), KCNQ4 (http://ghr.nlm.nih.gov/gene=kcnq4), LHFPL5 (http://ghr.nlm.nih.gov/gene=lhfpl5), MT-TS1 (http://ghr.nlm.nih.gov/gene=mtts1), MYO15A (http://ghr.nlm.nih.gov/gene=myo15a), MYO6 (http://ghr.nlm.nih.gov/gene=myo6), MYO7A

Studies

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(http://ghr.nlm.nih.gov/gene=myo7a), OTOF (http://ghr.nlm.nih.gov/gene=otof), PCDH15 (http://ghr.nlm.nih.gov/gene=pcdh15), POU3F4 (http://ghr.nlm.nih.gov/gene=pou3f4), SLC26A4 (http://ghr.nlm.nih.gov/gene=slc26a4), STRC (http://ghr.nlm.nih.gov/gene=strc), TECTA (http://ghr.nlm.nih.gov/gene=tecta), TMC1 (http://ghr.nlm.nih.gov/gene=tmc1), TMIE (http://ghr.nlm.nih.gov/gene=tmie), TMPRSS3 (http://ghr.nlm.nih.gov/gene=tmprss3), TRIOBP (http://ghr.nlm.nih.gov/gene=triobp), USH1C (http://ghr.nlm.nih.gov/gene=ush1c), and WFS1 (http://ghr.nlm.nih.gov/gene=wfs1) genes cause nonsyndromic deafness. Variations of the MT-RNR1 (http://ghr.nlm.nih.gov/gene=mtrnr1) gene increase the risk of developing nonsyndromic deafness. Variations in the ATP2B2 (http://ghr.nlm.nih.gov/gene=atp2b2) gene modify the course of nonsyndromic deafness. The GJB3 (http://ghr.nlm.nih.gov/gene=gjb3) and MYO1A (http://ghr.nlm.nih.gov/gene=myo1a) genes are associated with nonsyndromic deafness. The causes of nonsyndromic deafness are complex. Researchers have identified more than 30 genes that, when mutated, may cause nonsyndromic deafness; however, some of these genes have not been fully characterized. Many genes related to deafness are involved in the development and function of the inner ear. Mutations in these genes result in hearing loss by interfering with critical steps in processing sound. Different mutations in the same gene can cause different types of hearing loss, and some genes are associated with both syndromic and nonsyndromic deafness. In many affected families, the gene responsible for hearing loss has not been found. Mutations in the GJB2 gene are a major cause of prelingual nonsyndromic deafness. This gene provides instructions for making a protein called connexin 26. The GJB6 gene also provides instructions for making a connexin protein, connexin 30. These proteins form parts (subunits) of channels called gap junctions, which allow communication between neighboring cells. Mutations in connexin proteins that make up gap junctions may affect the function or survival of cells that are needed for hearing. DFN3 deafness is caused by mutations in the POU3F4 gene, which is located on the X chromosome. In people with this condition, one of the small bones in the middle ear (the stapes) cannot move normally, which interferes with hearing. This characteristic sign of DFN3 is called stapes fixation. At least four other regions of the X chromosome are involved in hearing loss, but the responsible genes have not been discovered. Alterations in the MT-RNR1 and MT-TS1 genes have been found to increase the risk of developing nonsyndromic deafness. These genes are found in mitochondria, which are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (called mitochondrial DNA). People with particular mutations in the MT-RNR1 gene have an increased risk of hearing loss if they are exposed to certain antibiotic medications called aminoglycosides; however, some people with a mutation in the MT-RNR1 gene develop hearing loss even without exposure to these antibiotics.

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Deafness can also result from environmental factors or a combination of genetic and environmental factors. Environmental causes of hearing loss include certain medications, specific infections before or after birth, and exposure to loud noise over an extended period.

How Do People Inherit Nonsyndromic Deafness? Nonsyndromic deafness can have different patterns of inheritance. Between 75 percent and 80 percent of cases are inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Usually, each parent of an individual with autosomal recessive deafness is a carrier of one copy of the altered gene, but is not affected by this form of hearing loss. Another 20 percent to 25 percent of nonsyndromic deafness cases are autosomal dominant, which means one copy of the altered gene in each cell is sufficient to result in hearing loss. People with autosomal dominant deafness most often inherit an altered copy of the gene from a parent who has hearing loss. Between 1 percent and 2 percent of cases show an X-linked pattern of inheritance, which means the mutated gene responsible for the condition is located on the X chromosome (one of the two sex chromosomes). Males with X-linked nonsyndromic deafness tend to develop more severe hearing loss earlier in life than females who inherit a copy of the same gene mutation. A striking characteristic of X-linked inheritance is that fathers cannot pass Xlinked traits to their sons. Mitochondrial nonsyndromic deafness, which results from changes to mitochondrial DNA, occurs in fewer than 1 percent of cases in the United States. The altered mitochondrial DNA is passed from a mother to all of her sons and daughters. This type of deafness is not inherited from fathers. Types of nonsyndromic deafness are named according to their inheritance patterns. Autosomal dominant forms are designated DFNA, autosomal recessive forms are DFNB, and X-linked forms are DFN. Each type is also numbered in the order in which it was described. For example, DFNA1 was the first described autosomal dominant type of nonsyndromic deafness. Mitochondrial nonsyndromic deafness does not have a special designation.

Where Can I Find Additional Information about Nonsyndromic Deafness? You may find the following resources about nonsyndromic deafness helpful. These materials are written for the general public. NIH Publications - National Institutes of Health •

National Center for Biotechnology Information: Genes and Disease: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gn d.section.123

Studies

•

National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/hearing/ MedlinePlus - Health Information

•

Encyclopedia: Age-related hearing loss: http://www.nlm.nih.gov/medlineplus/ency/article/001045.htm

•

Encyclopedia: Audiology: http://www.nlm.nih.gov/medlineplus/ency/article/003341.htm

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Encyclopedia: Hearing loss: http://www.nlm.nih.gov/medlineplus/ency/article/003044.htm

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Encyclopedia: Hearing or speech impairment - resources: http://www.nlm.nih.gov/medlineplus/ency/article/002152.htm

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Health Topic: Hearing Disorders and Deafness: http://www.nlm.nih.gov/medlineplus/hearingdisordersanddeafness.html

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Health Topic: Hearing Problems in Children: http://www.nlm.nih.gov/medlineplus/hearingproblemsinchildren.html Educational Resources - Information Pages

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American Academy of Audiology: Newborn Hearing Screening: http://www.audiology.org/aboutaudiology/consumered/guides/EHDI.htm

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American Academy of Otolaryngology--Head and Neck Surgery: Your Genes and Hearing Loss: http://www.aaohns.org/healthinfo/hearing/Genetic_Hearing_Loss.cfm

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Ask the Geneticist: Inheritance of deafness: http://www.askthegen.org/question.php?question_id=472

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Centers for Disease Control and Prevention: The Genetics of Infant Hearing Loss: http://www.cdc.gov/ncbddd/ehdi/genetics.htm

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Children's Hospital Boston: http://www.childrenshospital.org/az/Site991/mainpageS991P0.html

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Cleveland Clinic Health Information Center: http://www.clevelandclinic.org/health/search/showdocuments.asp?mediaID=5&topicId=804

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Harvard Medical School Center for Hereditary Deafness: http://hearing.harvard.edu/info/guides.htm

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Hereditary Hearing Loss (2nd Manual of Pediatric Otorhinolaryngology IAPO/IFOS): http://www.iapo.org.br/eng/manual/partes/ear/33.pdf

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Kennedy Krieger Institute: http://www.kennedykrieger.org/kki_diag.jsp?pid=1088

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KidsHealth from the Nemours Foundation: http://kidshealth.org/kid/health_problems/sight/hearing_impairment.html

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Laurent Clerc National Deaf Education Center, Gallaudet University: http://clerccenter.gallaudet.edu

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Mayo Clinic: http://www.mayoclinic.org/hearing-disorders/

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Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec19/ch218/ch218a.html

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Orphanet: Autosomal dominant nonsyndromic deafness: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=835

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Orphanet: Autosomal recessive nonsyndromic deafness: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=837

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Orphanet: Mitochondrial nonsyndromic deafness: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=26105

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Orphanet: X-linked nonsyndromic deafness: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=836

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The Connexin-Deafness Homepage: http://davinci.crg.es/deafness/

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The Wellcome Trust: http://genome.wellcome.ac.uk/doc_WTD020839.html Patient Support - for Patients and Families

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Alexander Graham Bell Association for the Deaf and Hard of Hearing: http://www.agbell.org/

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American Speech-Language-Hearing Association: http://www.asha.org

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DeafDOC.org: http://www.deafdoc.org/

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Deafness Research Foundation: http://www.drf.org/

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Deafness Research UK: http://www.deafnessresearch.org.uk/

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Hearing Loss Association of America: http://www.hearingloss.org/

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John Tracy Clinic: http://www.jtc.org

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March of Dimes: http://www.marchofdimes.com/professionals/14332_1232.asp

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My Baby's Hearing, Boys Town National Research Hospital: http://www.babyhearing.org/

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National Association of the Deaf: http://www.nad.org

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National Center for Hearing Assessment and Management, Utah State University: http://www.infanthearing.org/

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Resource list from the University of Kansas Medical Center: http://www.kumc.edu/gec/support/hearing.html

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Professional Resources You may also be interested in these resources, which are designed for healthcare professionals and researchers. •

Gene Reviews - Clinical summary: http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness/show/Gene+Reviews;jsessi onid=69A929A63846F53F5C2A13395CDE0486

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Gene Tests - DNA tests ordered by healthcare professionals: http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness/show/Gene+Tests;jsessioni d=69A929A63846F53F5C2A13395CDE0486

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Genetic Tools - Teaching cases: http://www.genetests.org/servlet/access?fcn=y&filename=/tools/cases/hearingLo ss-10/

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ACTion Sheets - Newborn screening follow up (1 link): http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness/show/ACTion+Sheets;jsessi onid=69A929A63846F53F5C2A13395CDE0486

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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22nonsyndromic+deafness%22+OR+%22 Hearing+Loss%22+OR+%22Deafness%22?recruiting=false

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PubMed - Recent literature: http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness/show/PubMed;jsessionid=6 9A929A63846F53F5C2A13395CDE0486

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Online Books - Medical and science texts: http://books.mcgrawhill.com/getommbid.php?isbn=0071459960&template=ommbid&c=254

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OMIM - Genetic disorder catalog: http://ghr.nlm.nih.gov/condition=nonsyndromicdeafness/show/OMIM;jsessionid=69 A929A63846F53F5C2A13395CDE0486

References These sources were used to develop the Genetics Home Reference condition summary on nonsyndromic deafness. •

Cremers CW, Snik AF, Huygen PL, Joosten FB, Cremers FP. X-linked mixed deafness syndrome with congenital fixation of the stapedial footplate and perilymphatic gusher (DFN3). Adv Otorhinolaryngol. 2002;61:161-7. No abstract available. PubMed citation

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del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Telleria D, Menendez I, Moreno F. A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med. 2002 Jan 24;346(4):243-9. PubMed citation

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Emery, Alan E H; Rimoin, David L; Emery & Rimoin's principles and practice of medical genetics.; 4th ed. / edited by David L. Rimoin. [et al.]; London; New York : Churchill Livingstone, 2002. p3637-3670. NLM Catalog

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Finsterer J, Fellinger J. Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing. Int J Pediatr Otorhinolaryngol. 2005 May;69(5):621-47. PubMed citation

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Friedman TB, Griffith AJ. Human nonsyndromic sensorineural deafness. Annu Rev Genomics Hum Genet. 2003;4:341-402. PubMed citation

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Gene Review: Deafness and Hereditary Hearing Loss Overview

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Gurtler N, Lalwani AK. Etiology of syndromic and nonsyndromic sensorineural hearing loss. Otolaryngol Clin North Am. 2002 Aug;35(4):891-908. Review. PubMed citation

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Hone SW, Smith RJ. Medical evaluation of pediatric hearing loss. Laboratory, radiographic, and genetic testing. Otolaryngol Clin North Am. 2002 Aug;35(4):751-64. Review. PubMed citation

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Kenneson A, Van Naarden Braun K, Boyle C. GJB2 (connexin 26) variants and nonsyndromic sensorineural hearing loss: a HuGE review. Genet Med. 2002 JulAug;4(4):258-74. Review. PubMed citation

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Li XC, Friedman RA. Nonsyndromic hereditary hearing loss. Otolaryngol Clin North Am. 2002 Apr;35(2):275-85. Review. PubMed citation

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Nance WE. The genetics of deafness. Ment Retard Dev Disabil Res Rev. 2003;9(2):109-19. PubMed citation

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Petersen MB, Willems PJ. Non-syndromic, autosomal-recessive deafness. Clin Genet. 2006 May;69(5):371-92. Review. PubMed citation

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Petersen MB. Non-syndromic autosomal-dominant deafness. Clin Genet. 2002 Jul;62(1):1-13. Review. PubMed citation

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Petit C. From deafness genes to hearing mechanisms: harmony and counterpoint. Trends Mol Med. 2006 Feb;12(2):57-64. Epub 2006 Jan 10. Review. PubMed citation

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Scriver, Charles R; The metabolic & molecular bases of inherited disease; 8th ed.; New York : McGraw-Hill, c2001. p6281-6328. NLM Catalog

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Van Camp G, Smith RJ. Maternally inherited hearing impairment. Clin Genet. 2000 Jun;57(6):409-14. Review. PubMed citation

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Van Laer L, Cryns K, Smith RJ, Van Camp G. Nonsyndromic hearing loss. Ear Hear. 2003 Aug;24(4):275-88. Review. PubMed citation

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Willems PJ. Genetic causes of hearing loss. N Engl J Med. 2000 Apr 13;342(15):1101-9. Review. No abstract available. PubMed citation

A summary of the chromosome and genes related to nonsyndromic deafness is provided below:

What Is Mitochondrial DNA?4 Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. In humans, mitochondrial DNA spans about 16,500 DNA building blocks (base pairs), representing a fraction of the total DNA in cells. 4

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/chromosome=MT;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. Oxidative phosphorylation is a process that uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. Mitochondrial genes are among the estimated 20,000 to 25,000 total genes in the human genome. There are genetic conditions related to mitochondrial genes.

What Conditions Are Related to Mitochondrial DNA? The following conditions are related to changes in mitochondrial DNA. Cancers Mitochondrial DNA is prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime and typically are not passed to future generations. Somatic mutations in mitochondrial DNA have been reported in some forms of cancer, including breast, colon, stomach, liver, and kidney tumors. These mutations also have been associated with cancer of blood-forming tissue (leukemia) and cancer of immune system cells (lymphoma). Leber Hereditary Optic Neuropathy Mutations in four mitochondrial genes, MT-ND1, MT-ND4, MT-ND4L, and MT-ND6, have been identified in people with Leber hereditary optic neuropathy. These genes provide instructions for making proteins that are part of a large enzyme complex. This group of enzymes, known as complex I, is necessary for oxidative phosphorylation. The mutations responsible for Leber hereditary optic neuropathy change single protein building blocks (amino acids) in these proteins, which may affect the generation of ATP within mitochondria. It remains unclear, however, why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain (the optic nerve). Additional genetic and environmental factors probably contribute to the vision loss and other medical problems associated with Leber hereditary optic neuropathy. Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Mutations in at least five mitochondrial genes, MT-ND1, MT-ND5, MT-TH, MT-TL1, and MT-TV, can cause the characteristic features of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Some of these genes provide instructions for making proteins that are part of a large enzyme complex, called complex I, that is necessary for oxidative phosphorylation. The other genes provide instructions for making transfer RNA molecules, which are essential for protein production within mitochondria.

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Neuropathy, Ataxia, and Retinitis Pigmentosa Mutations in one mitochondrial gene, MT-ATP6, have been found in people with neuropathy, ataxia, and retinitis pigmentosa (NARP). The MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function. This protein forms one part (subunit) of an enzyme called ATP synthase. This enzyme, which is also known as complex V, is responsible for the last step of oxidative phosphorylation, in which a molecule called adenosine diphosphate (ADP) is converted to ATP. Mutations in the MT-ATP6 gene alter the structure or function of ATP synthase, reducing the ability of mitochondria to make ATP. It is unclear how this disruption in mitochondrial energy production leads to muscle weakness, vision loss, and the other specific features of NARP. Nonsyndromic Deafness Mutations in two mitochondrial genes, MT-RNR1 and MT-TS1, are associated with nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body). These genes provide instructions for making types of RNA. The MTRNR1 gene provides instructions for a specific type of ribosomal RNA called 12S RNA. A particular form of transfer RNA, designated as tRNASer(UCN), is formed from the MT-TS1 gene. Both of these RNA molecules help assemble amino acids into full-length, functioning proteins within mitochondria. Other Disorders Inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body's systems. These mutations disrupt the mitochondria's ability to efficiently generate energy for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, some frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision.

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Is There a Standard Way to Diagram Mitochondrial DNA? Mitochondrial DNA is typically diagrammed as a circular structure with genes and regulatory regions labeled.

You may find the following resources about mitochondrial DNA helpful. These materials are written for the general public. You may also be interested in these resources, which are designed for genetics professionals and researchers.

References These sources were used to develop the Genetics Home Reference chromosome summary on mitochondrial DNA. •

Dimauro S, Davidzon G. Mitochondrial DNA and disease. Ann Med. 2005;37(3):222-32. Review. PubMed citation

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DiMauro S. Mitochondrial diseases. Biochim Biophys Acta. 2004 Jul 23;1658(1-2):80-8. Review. PubMed citation

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Fischel-Ghodsian N, Kopke RD, Ge X. Mitochondrial dysfunction in hearing loss. Mitochondrion. 2004 Sep;4(5-6):675-94. Epub 2004 Nov 6. PubMed citation

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Fischel-Ghodsian N. Mitochondrial deafness. Ear Hear. 2003 Aug;24(4):303-13. Review. PubMed citation

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Gene Review: Mitochondrial Disorders Overview

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Guan MX. Molecular pathogenetic mechanism of maternally inherited deafness. Ann N Y Acad Sci. 2004 Apr;1011:259-71. PubMed citation

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Kang D, Hamasaki N. Alterations of mitochondrial DNA in common diseases and disease states: aging, neurodegeneration, heart failure, diabetes, and cancer. Curr Med Chem. 2005;12(4):429-41. Review. PubMed citation

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McFarland R, Taylor RW, Turnbull DM. The neurology of mitochondrial DNA disease. Lancet Neurol. 2002 Oct;1(6):343-51. Review. PubMed citation

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McKenzie M, Liolitsa D, Hanna MG. Mitochondrial disease: mutations and mechanisms. Neurochem Res. 2004 Mar;29(3):589-600. Review. PubMed citation

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Penta JS, Johnson FM, Wachsman JT, Copeland WC. Mitochondrial DNA in human malignancy. Mutat Res. 2001 May;488(2):119-33. Review. PubMed citation

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Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nat Rev Genet. 2005 May;6(5):389-402. Review. PubMed citation

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Wallace DC. Mitochondrial diseases in man and mouse. Science. 1999 Mar 5;283(5407):1482-8. Review. PubMed citation

What Is the Official Name of the ACTG1 Gene?5 The official name of this gene is “actin, gamma 1.” ACTG1 is the gene's official symbol. The ACTG1 gene is also known by other names, listed below.

What Is the Normal Function of the ACTG1 Gene? The ACTG1 gene provides instructions for making a protein called gamma-actin 1, which is part of the actin protein family. Actin proteins are important for cell movement and the tensing action in muscles (muscle contractions). These proteins also help maintain the cytoskeleton, which is the structural framework that determines cell shape and organizes cell contents. Gamma-actin 1 is found in cells throughout the body, but it is particularly abundant in the cytoskeleton of certain cells in the intestines and the inner ear. Within the inner ear, gamma-actin 1 is found in specialized cells called hair cells, which play an important role in the hearing process.

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=actg1.

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What Conditions Are Related to the ACTG1 Gene? Nonsyndromic Deafness - Caused by Mutations in the ACTG1 Gene Researchers have identified several ACTG1 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA20. These mutations change one of the protein building blocks (amino acids) used to make gamma-actin 1, which most likely alters the 3-dimensional shape of the protein. The altered protein probably causes hearing loss by impairing the function or survival of hair cells.

Where Is the ACTG1 Gene Located? Cytogenetic Location: 17q25 Molecular Location on chromosome 17: base pairs 77,091,593 to 77,094,421

The ACTG1 gene is located on the long (q) arm of chromosome 17 at position 25. More precisely, the ACTG1 gene is located from base pair 77,091,593 to base pair 77,094,421 on chromosome 17.

References These sources were used to develop the Genetics Home Reference gene summary on the ACTG1 gene. •

OMIM

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Rendtorff ND, Zhu M, Fagerheim T, Antal TL, Jones M, Teslovich TM, Gillanders EM, Barmada M, Teig E, Trent JM, Friderici KH, Stephan DA, Tranebjaerg L. A novel missense mutation in ACTG1 causes dominant deafness in a Norwegian DFNA20/26 family, but ACTG1 mutations are not frequent among families with hereditary hearing impairment. Eur J Hum Genet. 2006 Jun 14; [Epub ahead of print]. PubMed citation

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van Wijk E, Krieger E, Kemperman MH, De Leenheer EM, Huygen PL, Cremers CW, Cremers FP, Kremer H. A mutation in the gamma actin 1 (ACTG1) gene causes

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autosomal dominant hearing loss (DFNA20/26). J Med Genet. 2003 Dec;40(12):879-84. PubMed citation •

Zhu M, Yang T, Wei S, DeWan AT, Morell RJ, Elfenbein JL, Fisher RA, Leal SM, Smith RJ, Friderici KH. Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26). Am J Hum Genet. 2003 Nov;73(5):108291. Epub 2003 Sep 16. PubMed citation

What Is the Official Name of the CDH23 Gene?6 The official name of this gene is “cadherin-like 23.” CDH23 is the gene's official symbol. The CDH23 gene is also known by other names, listed below.

What Is the Normal Function of the CDH23 Gene? The CDH23 gene provides instructions for making a protein called cadherin 23, a type of protein that helps cells stick together. Different cell types make different versions of this protein, including a short version in the light-sensitive layer in the back of the eye (the retina) and a longer version in the inner ear. Cadherin 23 interacts with other proteins in the cell membrane to carry out its normal role in cell attachment. Research suggests that this protein complex shapes inner ear structures called hair bundles. These structures are made of stereocilia, which are hairlike projections that bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses, which is an essential process for normal hearing. This protein complex may organize hair bundles by cross-linking the stereocilia and helping to promote the transmission of sound waves. In the retina, the role of the cadherin 23 protein complex is less well understood. Its presence in specialized cells that detect light and color (photoreceptor cells) in the retina suggests that it plays a critical role in the development and function of these cells.

What Conditions Are Related to the CDH23 Gene? Nonsyndromic Deafness - Caused by Mutations in the CDH23 Gene Approximately 20 mutations in the CDH23 gene have been identified in people with a type of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB12. Most of these mutations change a single protein building block (amino acid) used to make cadherin 23. These mutations disrupt the normal structure and function of this protein. Without adequate cadherin 23, deafness results because of improper development of the stereocilia in the inner ear.

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=cdh23;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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Usher Syndrome - Caused by Mutations in the CDH23 Gene Approximately 20 mutations in the CDH23 gene have been identified in people with a type of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB12. Most of these mutations change a single protein building block (amino acid) used to make cadherin 23. These mutations disrupt the normal structure and function of this protein. Without adequate cadherin 23, deafness results because of improper development of the stereocilia in the inner ear.

Where Is the CDH23 Gene Located? Cytogenetic Location: 10q21-q22 Molecular Location on chromosome 10: base pairs 72,826,696 to 73,245,658

The CDH23 gene is located on the long (q) arm of chromosome 10 between positions 21 and 22. More precisely, the CDH23 gene is located from base pair 72,826,696 to base pair 73,245,658 on chromosome 10.

References These sources were used to develop the Genetics Home Reference gene summary on the CDH23 gene. •

Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER. The molecular genetics of Usher syndrome. Clin Genet. 2003 Jun;63(6):431-44. PubMed citation

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Astuto LM, Bork JM, Weston MD, Askew JW, Fields RR, Orten DJ, Ohliger SJ, Riazuddin S, Morell RJ, Khan S, Riazuddin S, Kremer H, van Hauwe P, Moller CG, Cremers CW, Ayuso C, Heckenlively JR, Rohrschneider K, Spandau U, Greenberg J, Ramesar R, Reardon W, Bitoun P, Millan J, Legge R, Friedman TB, Kimberling WJ. CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet. 2002 Aug;71(2):262-75. Epub 2002 Jun 19. PubMed citation

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Boeda B, El-Amraoui A, Bahloul A, Goodyear R, Daviet L, Blanchard S, Perfettini I, Fath KR, Shorte S, Reiners J, Houdusse A, Legrain P, Wolfrum U, Richardson G, Petit C. Myosin VIIa, harmonin and cadherin 23, three Usher I gene products that cooperate to shape the sensory hair cell bundle. EMBO J. 2002 Dec 16;21(24):6689-99. PubMed citation

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Bolz H, von Brederlow B, Ramirez A, Bryda EC, Kutsche K, Nothwang HG, Seeliger M, del C-Salcedo Cabrera M, Vila MC, Molina OP, Gal A, Kubisch C. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet. 2001 Jan;27(1):108-12. PubMed citation

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Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, Polomeno R, Ramesh A, Schloss M, Srisailpathy CR, Wayne S, Bellman S, Desmukh D, Ahmed Z, Khan SN, Kaloustian VM, Li XC, Lalwani A, Riazuddin S, Bitner-Glindzicz M, Nance WE, Liu XZ, Wistow G, Smith RJ, Griffith AJ, Wilcox ER, Friedman TB, Morell RJ. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet. 2001 Jan;68(1):26-37. Epub 2000 Nov 21. PubMed citation

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El-Amraoui A, Petit C. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci. 2005 Oct 15;118(Pt 20):4593-603. Review. PubMed citation

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Keats BJ, Savas S. Genetic heterogeneity in Usher syndrome. Am J Med Genet A. 2004 Sep 15;130(1):13-6. Review. PubMed citation

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Lagziel A, Ahmed ZM, Schultz JM, Morell RJ, Belyantseva IA, Friedman TB. Spatiotemporal pattern and isoforms of cadherin 23 in wild type and waltzer mice during inner ear hair cell development. Dev Biol. 2005 Apr 15;280(2):295-306. PubMed citation

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Pennings RJ, Topsakal V, Astuto L, de Brouwer AP, Wagenaar M, Huygen PL, Kimberling WJ, Deutman AF, Kremer H, Cremers CW. Variable clinical features in patients with CDH23 mutations (USH1D-DFNB12). Otol Neurotol. 2004 Sep;25(5):699706. PubMed citation

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Reiners J, Nagel-Wolfrum K, Jurgens K, Marker T, Wolfrum U. Molecular basis of human Usher syndrome: deciphering the meshes of the Usher protein network provides insights into the pathomechanisms of the Usher disease. Exp Eye Res. 2006 Jul;83(1):97119. Epub 2006 Mar 20. Review. PubMed citation

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Siemens J, Kazmierczak P, Reynolds A, Sticker M, Littlewood-Evans A, Muller U. The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZdomain interactions. Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14946-51. Epub 2002 Oct 29. PubMed citation

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Siemens J, Lillo C, Dumont RA, Reynolds A, Williams DS, Gillespie PG, Muller U. Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature. 2004 Apr 29;428(6986):950-5. Epub 2004 Mar 31. PubMed citation

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Zheng QY, Yan D, Ouyang XM, Du LL, Yu H, Chang B, Johnson KR, Liu XZ. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet. 2005 Jan 1;14(1):103-11. Epub 2004 Nov 10. PubMed citation

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What Is the Official Name of the CLDN14 Gene?7 The official name of this gene is “claudin 14.” CLDN14 is the gene's official symbol. The CLDN14 gene is also known by other names, listed below.

What Is the Normal Function of the CLDN14 Gene? The CLDN14 gene provides instructions for making a protein called claudin 14. This protein is a member of the claudin protein family, which provides building components for tight junctions. Tight junctions seal the space between cells, creating a barrier that restricts the passage of fluids and certain particles in and out of cells. For example, tight junctions prevent digestive enzymes in intestinal cells from leaking into the blood. Claudin 14 is found in the liver, kidneys, and inner ear, but its exact function is unclear. In the inner ear, this protein probably plays a role in converting sound waves to nerve impulses, a critical process for normal hearing. This conversion process requires the proper level of charged atoms (ions). Researchers suggest that tight junctions composed of claudin 14 help to maintain these ion levels.

What Conditions Are Related to the CLDN14 Gene? Nonsyndromic Deafness - Caused by Mutations in the CLDN14 Gene Researchers have identified a few CLDN14 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB29. One mutation deletes a single DNA building block (base pair), which disrupts the instructions for producing claudin 14. The remaining mutations change one of the protein building blocks (amino acids) used to make claudin 14. These changes probably alter the structure of claudin 14, which could impair the protein's ability to form tight junctions. Improper ion levels may result from missing or altered tight junctions, which could disrupt processes required for normal hearing.

Where Is the CLDN14 Gene Located? Cytogenetic Location: 21q22.3 Molecular Location on chromosome 21: base pairs 36,754,788 to 36,774,257

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=cldn14.

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The CLDN14 gene is located on the long (q) arm of chromosome 21 at position 22.3. More precisely, the CLDN14 gene is located from base pair 36,754,788 to base pair 36,774,257 on chromosome 21.

References These sources were used to develop the Genetics Home Reference gene summary on the CLDN14 gene. •

Ben-Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Van Itallie CM, Beyer LA, Halsey K, Gardner DJ, Wilcox ER, Rasmussen J, Anderson JM, Dolan DF, Forge A, Raphael Y, Camper SA, Friedman TB. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet. 2003 Aug 15;12(16):2049-61. PubMed citation

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OMIM

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Wattenhofer M, Reymond A, Falciola V, Charollais A, Caille D, Borel C, Lyle R, Estivill X, Petersen MB, Meda P, Antonarakis SE. Different mechanisms preclude mutant CLDN14 proteins from forming tight junctions in vitro. Hum Mutat. 2005 Jun;25(6):5439. PubMed citation

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Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, Belyantseva I, BenYosef T, Liburd NA, Morell RJ, Kachar B, Wu DK, Griffith AJ, Riazuddin S, Friedman TB. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell. 2001 Jan 12;104(1):165-72. PubMed citation

What Is the Official Name of the COCH Gene?8 The official name of this gene is “coagulation factor C homolog, cochlin (Limulus polyphemus).”

8

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=coch;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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COCH is the gene's official symbol. The COCH gene is also known by other names, listed below.

What Is the Normal Function of the COCH Gene? The COCH gene provides instructions for making a protein called cochlin. This protein is abundant in certain parts of the inner ear called the cochlea and the vestibular system. The cochlea is a snail-shaped structure that helps process sound, and the vestibular system consists of fluid-filled canals that help maintain the body's balance and orientation in space. Cochlin is exported from cells in the cochlea and vestibular system and becomes part of the extracellular matrix. The extracellular matrix is an intricate lattice that forms in the space between cells and provides structural support. Two regions of the cochlin protein, called the LCCL and vWFA domains, probably coordinate cochlin's interactions with other molecules in the extracellular matrix. These interactions are important in forming the extracellular matrix and keeping it organized. Although the exact role of cochlin remains unknown, it likely plays a role in the structure of the inner ear.

What Conditions Are Related to the COCH Gene? Nonsyndromic Deafness - Caused by Mutations in the COCH Gene Several COCH mutations have been identified in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA9. These mutations either change or delete a protein building block (amino acid) used to make cochlin. Most of the reported COCH mutations affect the LCCL domain and probably impair cochlin's interactions with other molecules in the extracellular matrix. One mutation occurs outside the LCCL domain and likely affects cochlin's 3-dimensional shape.

Where Is the COCH Gene Located? Cytogenetic Location: 14q12-q13 Molecular Location on chromosome 14: base pairs 30,413,515 to 30,429,572

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The COCH gene is located on the long (q) arm of chromosome 14 between positions 12 and 13. More precisely, the COCH gene is located from base pair 30,413,515 to base pair 30,429,572 on chromosome 14.

References These sources were used to develop the Genetics Home Reference gene summary on the COCH gene. •


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Grabski R, Szul T, Sasaki T, Timpl R, Mayne R, Hicks B, Sztul E. Mutations in COCH that result in non-syndromic autosomal dominant deafness (DFNA9) affect matrix deposition of cochlin. Hum Genet. 2003 Oct;113(5):406-16. Epub 2003 Aug 20. PubMed citation

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Ikezono T, Shindo S, Li L, Omori A, Ichinose S, Watanabe A, Kobayashi T, Pawankar R, Yagi T. Identification of a novel Cochlin isoform in the perilymph: insights to Cochlin function and the pathogenesis of DFNA9. Biochem Biophys Res Commun. 2004 Feb 6;314(2):440-6. PubMed citation

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Nagy I, Horvath M, Trexler M, Repassy G, Patthy L. A novel COCH mutation, V104del, impairs folding of the LCCL domain of cochlin and causes progressive hearing loss. J Med Genet. 2004 Jan;41(1):e9. No abstract available. PubMed citation

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Robertson NG, Cremers CW, Huygen PL, Ikezono T, Krastins B, Kremer H, Kuo SF, Liberman MC, Merchant SN, Miller CE, Nadol JB Jr, Sarracino DA, Verhagen WI, Morton CC. Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum Mol Genet. 2006 Apr 1;15(7):1071-85. Epub 2006 Feb 15. PubMed citation

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Robertson NG, Hamaker SA, Patriub V, Aster JC, Morton CC. Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9. J Med Genet. 2003 Jul;40(7):479-86. PubMed citation

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Street VA, Kallman JC, Robertson NG, Kuo SF, Morton CC, Phillips JO. A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and sitespecific vestibular and central oculomotor dysfunction. Am J Med Genet A. 2005 Dec 1;139(2):86-95. PubMed citation

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What Is the Official Name of the COL11A2 Gene?9 The official name of this gene is “collagen, type XI, alpha 2.” COL11A2 is the gene's official symbol. The COL11A2 gene is also known by other names, listed below.

What Is the Normal Function of the COL11A2 Gene? The COL11A2 gene, along with several other genes, provides instructions for the production of type XI collagen. The COL11A2 gene produces one component of this type of collagen, called the pro-alpha2(XI) chain. Type XI collagen adds structure and strength to the tissues that support the body's muscles, joints, organs, and skin (the connective tissue). Type XI collagen is normally found in cartilage, the tissue that cushions bones and joints and makes up the flexible portions of the nose and ears. It is also part of the jelly-like substance that fills the eyeball (the vitreous), the inner ear, and the center portion of the discs between the vertebrae in the spine (nucleus pulposus). The pro-alpha2(XI) chain combines with two other collagen chains (pro-alpha1(XI) and proalpha1(II)) to form a procollagen molecule. These triple-stranded, ropelike procollagen molecules must be processed by enzymes in the cell. Once processed, these procollagen molecules leave the cell and arrange themselves into long, thin fibrils that cross-link to one another in the spaces around cells. The cross-linkages result in the formation of very strong mature type XI collagen fibers. Type XI collagen also helps maintain the spacing and diameter of type II collagen fibrils. Type II collagen is an important component of the eye and mature cartilage tissue. The size and arrangement of type II collagen fibrils are essential for the normal structure of these tissues.

9

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=col11a2.

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What Conditions Are Related to the COL11A2 Gene? Nonsyndromic Deafness - Caused by Mutations in the COL11A2 Gene Mutations in the COL11A2 gene cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA13. This type of deafness has been identified in two large families. In one family, a mutation replaces the amino acid arginine (a building block of proteins) with the amino acid cysteine at position 549 in the alpha 2 chain of type XI collagen. This mutation is written as Arg549Cys. A second family has a mutation that substitutes the amino acid glutamic acid for the amino acid glycine at position 323 (written as Gly323Glu) in this protein. These mutations prevent the normal assembly of type XI collagen, which plays an important role in the structure and function of the inner ear. Otospondylomegaepiphyseal Dysplasia - Caused by Mutations in the COL11A2 Gene Mutations in the COL11A2 gene cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA13. This type of deafness has been identified in two large families. In one family, a mutation replaces the amino acid arginine (a building block of proteins) with the amino acid cysteine at position 549 in the alpha 2 chain of type XI collagen. This mutation is written as Arg549Cys. A second family has a mutation that substitutes the amino acid glutamic acid for the amino acid glycine at position 323 (written as Gly323Glu) in this protein. These mutations prevent the normal assembly of type XI collagen, which plays an important role in the structure and function of the inner ear. Stickler Syndrome - Caused by Mutations in the COL11A2 Gene Approximately 10 mutations identified in the COL11A2 gene are responsible for otospondylomegaepiphyseal dysplasia (OSMED), a bone growth disorder. Most of these mutations result in a complete lack of pro-alpha2(XI) chains, which leads to a loss of function of type XI collagen. Some mutations affect the production of the pro-alpha2(XI) chain and disrupt the assembly of type XI collagen. Type XI collagen is an important component of cartilage and other connective tissues, and its loss or impairment results in the characteristic signs and symptoms of OSMED. Weissenbacher-Zweymüller Syndrome - Caused by Mutations in the COL11A2 Gene Stickler syndrome is a disorder that causes problems with skeletal development, vision, and hearing. Mutations in the COL11A2 gene cause a form of Stickler syndrome in which vision is not affected. COL11A2 mutations cause abnormal production of the pro-alpha2(XI) chain, part of type XI collagen. As a result, type XI collagen is impaired and cannot function properly, causing the skeletal and hearing problems characteristic of Stickler syndrome. The pro-alpha2(XI) chain, however, is not made in the eyes. Instead, another type of collagen chain replaces pro-alpha2(XI) to form type XI collagen in the vitreous of the eye. COL11A2 mutations, therefore, do not affect vision.

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Other Disorders - Increased Risk from Variations of the COL11A2 Gene At least one identified mutation in the COL11A2 gene is responsible for WeissenbacherZweymüller syndrome. This mutation causes the amino acid glycine to be replaced with the amino acid glutamic acid at position 955 in the alpha 2 chain of type XI collagen (written as Gly955Glu). This mutation prevents collagen molecules from being assembled properly, which disrupts the structure of type XI collagen. These changes result in the characteristic signs and symptoms of Weissenbacher-Zweymüller syndrome, including short stature, distinctive facial features, and sometimes hearing loss.

Where Is the COL11A2 Gene Located? Cytogenetic Location: 6p21.3 Molecular Location on chromosome 6: base pairs 33,238,446 to 33,268,222

The COL11A2 gene is located on the short (p) arm of chromosome 6 at position 21.3. More precisely, the COL11A2 gene is located from base pair 33,238,446 to base pair 33,268,222 on chromosome 6.

References These sources were used to develop the Genetics Home Reference gene summary on the COL11A2 gene. •

De Leenheer EM, Kunst HH, McGuirt WT, Prasad SD, Brown MR, Huygen PL, Smith RJ, Cremers CW. Autosomal dominant inherited hearing impairment caused by a missense mutation in COL11A2 (DFNA13). Arch Otolaryngol Head Neck Surg. 2001 Jan;127(1):13-7. PubMed citation

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Entrez Gene

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Jakkula E, Melkoniemi M, Kiviranta I, Lohiniva J, Raina SS, Perala M, Warman ML, Ahonen K, Kroger H, Goring HH, Ala-Kokko L. The role of sequence variations within the genes encoding collagen II, IX and XI in non-syndromic, early-onset osteoarthritis. Osteoarthritis Cartilage. 2005 Jun;13(6):497-507. PubMed citation

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Li SW, Takanosu M, Arita M, Bao Y, Ren ZX, Maier A, Prockop DJ, Mayne R. Targeted disruption of Col11a2 produces a mild cartilage phenotype in transgenic mice: comparison with the human disorder otospondylomegaepiphyseal dysplasia (OSMED). Dev Dyn. 2001 Oct;222(2):141-52. PubMed citation

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McGuirt WT, Prasad SD, Griffith AJ, Kunst HP, Green GE, Shpargel KB, Runge C, Huybrechts C, Mueller RF, Lynch E, King MC, Brunner HG, Cremers CW, Takanosu M, Li SW, Arita M, Mayne R, Prockop DJ, Van Camp G, Smith RJ. Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat Genet. 1999 Dec;23(4):413-9. PubMed citation

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Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kaariainen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L. Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene. Am J Hum Genet. 2000 Feb;66(2):36877. PubMed citation

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Melkoniemi M, Koillinen H, Mannikko M, Warman ML, Pihlajamaa T, Kaariainen H, Rautio J, Hukki J, Stofko JA, Cisneros GJ, Krakow D, Cohn DH, Kere J, Ala-Kokko L. Collagen XI sequence variations in nonsyndromic cleft palate, Robin sequence and micrognathia. Eur J Hum Genet. 2003 Mar;11(3):265-70. PubMed citation

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OMIM: COL11A2

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Pihlajamaa T, Prockop DJ, Faber J, Winterpacht A, Zabel B, Giedion A, Wiesbauer P, Spranger J, Ala-Kokko L. Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymuller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet. 1998 Nov 2;80(2):115-20. PubMed citation

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Shpargel KB, Makishima T, Griffith AJ. Col11a1 and Col11a2 mRNA expression in the developing mouse cochlea: implications for the correlation of hearing loss phenotype with mutant type XI collagen genotype. Acta Otolaryngol. 2004 Apr;124(3):242-8. PubMed citation

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Snead MP. Hereditary vitreopathy. Eye. 1996;10 ( Pt 6):653-63. Review. PubMed citation

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van Steensel MA, Buma P, de Waal Malefijt MC, van den Hoogen FH, Brunner HG. Otospondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene. Am J Med Genet. 1997 Jun 13;70(3):315-23. PubMed citation

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Vuoristo MM, Pappas JG, Jansen V, Ala-Kokko L. A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome. Am J Med Genet A. 2004 Oct 1;130(2):160-4. Review. PubMed citation

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What Is the Official Name of the DFNA5 Gene?10 The official name of this gene is “deafness, autosomal dominant 5.” DFNA5 is the gene's official symbol. The DFNA5 gene is also known by other names, listed below.

What Is the Normal Function of the DFNA5 Gene? The DFNA5 gene provides instructions for producing the DFNA5 protein, which appears to be important for normal hearing. Researchers believe that this protein plays a role in the development and maintenance of the cochlea, a snail-shaped structure in the inner ear that converts sound waves into nerve impulses. The specific function of this protein is not known, however.

What Conditions Are Related to the DFNA5 Gene? Nonsyndromic Deafness - Caused by Mutations in the DFNA5 Gene At least three mutations in the DFNA5 gene have been identified in a small number of families with nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA5. These mutations cause an abnormally shortened version of the DFNA5 protein to be made. Families affected by mutations in this gene experience progressive hearing loss that resembles age-related hearing loss (presbyacusis). Generally, hearing loss begins at an earlier age in people with DFNA5 mutations compared to people without a DFNA5 mutation.

Where Is the DFNA5 Gene Located? Cytogenetic Location: 7p15 Molecular Location on chromosome 7: base pairs 24,704,499 to 24,763,887

10

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=dfna5;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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The DFNA5 gene is located on the short (p) arm of chromosome 7 at position 15. More precisely, the DFNA5 gene is located from base pair 24,704,499 to base pair 24,763,887 on chromosome 7.

References These sources were used to develop the Genetics Home Reference gene summary on the DFNA5 gene. •

Bischoff AM, Luijendijk MW, Huygen PL, van Duijnhoven G, De Leenheer EM, Oudesluijs GG, Van Laer L, Cremers FP, Cremers CW, Kremer H. A novel mutation identified in the DFNA5 gene in a Dutch family: a clinical and genetic evaluation. Audiol Neurootol. 2004 Jan-Feb;9(1):34-46. PubMed citation

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Entrez Gene

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OMIM: Autosomal Dominant Nonsyndromic Sensorineural Deafness 5

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Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, Van de Heyning P, McGuirt WT, Smith RJ, Willems PJ, Legan PK, Richardson GP, Van Camp G. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nat Genet. 1998 Oct;20(2):194-7. PubMed citation

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Van Laer L, Vrijens K, Thys S, Van Tendeloo VF, Smith RJ, Van Bockstaele DR, Timmermans JP, Van Camp G. DFNA5: hearing impairment exon instead of hearing impairment gene? J Med Genet. 2004 Jun;41(6):401-6. PubMed citation

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Yu C, Meng X, Zhang S, Zhao G, Hu L, Kong X. A 3-nucleotide deletion in the polypyrimidine tract of intron 7 of the DFNA5 gene causes nonsyndromic hearing impairment in a Chinese family. Genomics. 2003 Nov;82(5):575-9. PubMed citation

What Is the Official Name of the DFNB31 Gene?11 The official name of this gene is “deafness, autosomal recessive 31.” DFNB31 is the gene's official symbol. The DFNB31 gene is also known by other names, listed below.

What Is the Normal Function of the DFNB31 Gene? The DFNB31 gene provides instructions for making a protein called whirlin. Whirlin belongs to a group of proteins that have specialized regions called PDZ domains. PDZ domains are sites of protein-protein interactions that are important for normal cell functions. 11

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=dfnb31.

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Whirlin is made in several types of cells, but it has been best studied in cells from the inner ear and the light-sensitive tissue at the back of the eye (the retina). In the inner ear, it appears that whirlin is needed for normal hearing. Hearing requires the conversion of sound waves to nerve impulses that are transmitted via the auditory nerve to the brain. Researchers suggest that whirlin plays an important role in the development and maintenance of stereocilia, the hairlike structures that project from specialized cells called hair cells. Stereocilia line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses. In the retina, whirlin's function is not well understood. Research findings indicate that it may be important in the development and function of photoreceptor cells, which detect light and color.

What Conditions Are Related to the DFNB31 Gene? Nonsyndromic Deafness - Caused by Mutations in the DFNB31 Gene Researchers have identified two mutations in the DFNB31 gene that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB31. These mutations introduce a premature stop signal in the instructions for making whirlin. As a result, no protein is produced, or an abnormally small protein that is missing a PDZ domain is made. The abnormal whirlin protein or the absence of whirlin probably impairs the function of stereocilia, leading to hearing loss.

Where Is the DFNB31 Gene Located? Cytogenetic Location: 9q32-q34 Molecular Location on chromosome 9: base pairs 116,204,180 to 116,307,525

The DFNB31 gene is located on the long (q) arm of chromosome 9 between positions 32 and 34. More precisely, the DFNB31 gene is located from base pair 116,204,180 to base pair 116,307,525 on chromosome 9.

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References These sources were used to develop the Genetics Home Reference gene summary on the DFNB31 gene. •

Mburu P, Kikkawa Y, Townsend S, Romero R, Yonekawa H, Brown SD. Whirlin complexes with p55 at the stereocilia tip during hair cell development. Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):10973-8. Epub 2006 Jul 7. PubMed citation

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Mburu P, Mustapha M, Varela A, Weil D, El-Amraoui A, Holme RH, Rump A, Hardisty RE, Blanchard S, Coimbra RS, Perfettini I, Parkinson N, Mallon AM, Glenister P, Rogers MJ, Paige AJ, Moir L, Clay J, Rosenthal A, Liu XZ, Blanco G, Steel KP, Petit C, Brown SD. Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. Nat Genet. 2003 Aug;34(4):421-8. PubMed citation

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OMIM

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Tlili A, Charfedine I, Lahmar I, Benzina Z, Mohamed BA, Weil D, Idriss N, Drira M, Masmoudi S, Ayadi H. Identification of a novel frameshift mutation in the DFNB31/WHRN gene in a Tunisian consanguineous family with hereditary nonsyndromic recessive hearing loss. Hum Mutat. 2005 May;25(5):503. PubMed citation

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van Wijk E, van der Zwaag B, Peters T, Zimmermann U, Te Brinke H, Kersten FF, Marker T, Aller E, Hoefsloot LH, Cremers CW, Cremers FP, Wolfrum U, Knipper M, Roepman R, Kremer H. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum Mol Genet. 2006 Mar 1;15(5):751-65. Epub 2006 Jan 24. PubMed citation

What Is the Official Name of the DFNB59 Gene?12 The official name of this gene is “deafness, autosomal recessive 59.” DFNB59 is the gene's official symbol. The DFNB59 gene is also known by other names, listed below.

What Is the Normal Function of the DFNB59 Gene? The DFNB59 gene provides instructions for making a protein called pejvakin. This protein is present in the nerves leading from the inner ear to the brain (auditory nerves). It is also found in the part of the brain that is connected to the spinal cord (the brainstem). Although the exact function of pejvakin is uncertain, it appears to be essential for normal hearing. Hearing requires the conversion of sound waves to nerve impulses that are transmitted via the auditory nerves to the brain. Researchers believe that pejvakin may play a role in the transmission of nerve impulses that register sound.

12

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=dfnb59;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Conditions Are Related to the DFNB59 Gene? Nonsyndromic Deafness - Caused by Mutations in the DFNB59 Gene Researchers have identified at least two DFNB59 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB59. People with these mutations have a type of hearing loss called auditory neuropathy, which occurs when sound is not transmitted properly from the inner ear to the brain.

Where Is the DFNB59 Gene Located? Cytogenetic Location: 2q31.2

The DFNB59 gene is located on the long (q) arm of chromosome 2 at position 31.2. You and your healthcare professional may find the following resources about DFNB59 helpful.

References These sources were used to develop the Genetics Home Reference gene summary on the DFNB59 gene. •

Delmaghani S, del Castillo FJ, Michel V, Leibovici M, Aghaie A, Ron U, Van Laer L, BenTal N, Van Camp G, Weil D, Langa F, Lathrop M, Avan P, Petit C. Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Nat Genet. 2006 Jul;38(7):770-8. Epub 2006 Jun 25. PubMed citation

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Entrez Gene

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OMIM

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What Is the Official Name of the ESPN Gene?13 The official name of this gene is “espin.” ESPN is the gene's official symbol. The ESPN gene is also known by other names, listed below.

What Is the Normal Function of the ESPN Gene? The ESPN gene provides instructions for making a protein called espin. This protein is active in the inner ear, where it appears to play an essential role in normal hearing and balance. Researchers believe that espin binds to actin, a protein that is important for cell movement and shape. Espin is probably involved in the growth and maintenance of hairlike projections called stereocilia. Stereocilia, which are rich in actin, line the inner ear and bend in response to sound waves. This bending motion is essential for converting sound waves to nerve impulses and for conveying information about the body's position and movement. Espin may also play a role in other types of sensory cells. Some studies suggest that this protein is present in taste receptor cells, cells involved in recognizing smells, and Merkel cells in the skin, which are associated with the sense of touch. In these cells, espin is located in small, fingerlike structures called microvilli that project from the cell surface. Like stereocilia in the inner ear, microvilli contain a large amount of actin.

What Conditions Are Related to the ESPN Gene? Nonsyndromic Deafness - Caused by Mutations in the ESPN Gene At least six mutations in the ESPN gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB36. Several of these mutations cause an autosomal recessive form of nonsyndromic deafness that includes problems with balance. Autosomal recessive inheritance means that two copies of the gene in each cell are altered. These genetic changes delete a small amount of DNA from critical regions of the ESPN gene. Researchers believe that these genetic changes may prevent the production of espin or lead to an abnormally small, nonfunctional version of the protein that cannot bind to actin. A loss of espin function likely disrupts the development, structure, and organization of stereocilia, leading to hearing loss and balance problems.

Where Is the ESPN Gene Located? Cytogenetic Location: 1p36.31-p36.11

13

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=espn.

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Molecular Location on chromosome 1: base pairs 6,407,434 to 6,443,575 The ESPN gene is located on the short (p) arm of chromosome 1 between positions 36.31 and 36.11.

References These sources were used to develop the Genetics Home Reference gene summary on the ESPN gene. •

Donaudy F, Zheng L, Ficarella R, Ballana E, Carella M, Melchionda S, Estivill X, Bartles JR, Gasparini P. Espin gene (ESPN) mutations associated with autosomal dominant hearing loss cause defects in microvillar elongation or organisation. J Med Genet. 2006 Feb;43(2):157-61. Epub 2005 Jun 1. PubMed citation

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Naz S, Griffith AJ, Riazuddin S, Hampton LL, Battey JF Jr, Khan SN, Riazuddin S, Wilcox ER, Friedman TB. Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J Med Genet. 2004 Aug;41(8):591-5. PubMed citation

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Sekerkova G, Zheng L, Loomis PA, Changyaleket B, Whitlon DS, Mugnaini E, Bartles JR. Espins are multifunctional actin cytoskeletal regulatory proteins in the microvilli of chemosensory and mechanosensory cells. J Neurosci. 2004 Jun 9;24(23):5445-56. PubMed citation

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Sekerkova G, Zheng L, Loomis PA, Mugnaini E, Bartles JR. Espins and the actin cytoskeleton of hair cell stereocilia and sensory cell microvilli. Cell Mol Life Sci. 2006 Aug 11; [Epub ahead of print]. PubMed citation

What Is the Official Name of the EYA4 Gene?14 The official name of this gene is “eyes absent homolog 4 (Drosophila).” EYA4 is the gene's official symbol. The EYA4 gene is also known by other names, listed below.

14

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=eya4;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Is the Normal Function of the EYA4 Gene? The EYA4 gene provides instructions for making a protein that plays a role in regulating the activity of other genes. Based on this role, the EYA4 protein is called a transcription factor or transcription coactivator. The EYA4 gene is active in the heart, inner ear, muscles, and other tissues throughout the body. Two regions of the EYA4 protein, called the Eya domain and the variable domain, are important for interactions with other proteins. These protein interactions help to control gene activities that appear to be important for heart function, development of the inner ear, and maintenance of normal hearing.

What Conditions Are Related to the EYA4 Gene? Nonsyndromic Deafness - Caused by Mutations in the EYA4 Gene A few EYA4 mutations have been reported in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA10. These mutations create a premature stop signal in the instructions for making the EYA4 protein. As a result, no protein is produced, or an abnormally small protein is made. The abnormal EYA4 protein lacks some or all of the Eya domain, which impairs interactions with other proteins. Impaired protein interactions probably disrupt the control of gene activities that are important for the development of the inner ear and maintenance of normal hearing. Other Disorders - Caused by Mutations in the EYA4 Gene A few EYA4 mutations have been reported in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA10. These mutations create a premature stop signal in the instructions for making the EYA4 protein. As a result, no protein is produced, or an abnormally small protein is made. The abnormal EYA4 protein lacks some or all of the Eya domain, which impairs interactions with other proteins. Impaired protein interactions probably disrupt the control of gene activities that are important for the development of the inner ear and maintenance of normal hearing.

Where Is the EYA4 Gene Located? Cytogenetic Location: 6q23

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Molecular Location on chromosome 6: base pairs 133,604,205 to 133,892,352 The EYA4 gene is located on the long (q) arm of chromosome 6 at position 23.

References These sources were used to develop the Genetics Home Reference gene summary on the EYA4 gene. •

De Leenheer EM, Huygen PL, Wayne S, Verstreken M, Declau F, Van Camp G, Van de Heyning PH, Smith RJ, Cremers CW. DFNA10/EYA4--the clinical picture. Adv Otorhinolaryngol. 2002;61:73-8. No abstract available. PubMed citation

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OMIM: EYA4

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Pfister M, Toth T, Thiele H, Haack B, Blin N, Zenner HP, Sziklai I, Murnberg P, Kupka S. A 4-bp Insertion in the eya-Homologous Region (eyaHR) of EYA4 Causes Hearing Impairment in a Hungarian Family Linked to DFNA10. Mol Med. 2002 Oct;8(10):607-11. PubMed citation

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Schonberger J, Wang L, Shin JT, Kim SD, Depreux FF, Zhu H, Zon L, Pizard A, Kim JB, Macrae CA, Mungall AJ, Seidman JG, Seidman CE. Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. Nat Genet. 2005 Apr;37(4):418-22. Epub 2005 Feb 27. PubMed citation

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Wayne S, Robertson NG, DeClau F, Chen N, Verhoeven K, Prasad S, Tranebjarg L, Morton CC, Ryan AF, Van Camp G, Smith RJ. Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum Mol Genet. 2001 Feb 1;10(3):195-200. PubMed citation

What Is the Official Name of the GJB2 Gene?15 The official name of this gene is “gap junction protein, beta 2, 26kDa (connexin 26).” 15

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=gjb2.

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GJB2 is the gene's official symbol. The GJB2 gene is also known by other names, listed below.

What Is the Normal Function of the GJB2 Gene? The GJB2 gene provides instructions for making a protein called gap junction beta 2, more commonly known as connexin 26. Connexin 26 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells. The size of the gap junction and the types of particles that move through it are determined by the particular connexin proteins that make up the channel. Gap junctions made with connexin 26 transport potassium ions and certain small molecules. Connexin 26 is found in cells throughout the body, particularly in the inner ear and the skin. Because of its presence in the inner ear, especially the snail-shaped structure called the cochlea, researchers are interested in this protein's role in hearing. Hearing requires the conversion of sound waves to electrical nerve impulses. This conversion involves many processes, including maintaining the proper level of potassium ions in the inner ear. Some studies indicate that channels made with connexin 26 help to maintain the correct level of potassium ions. Other research suggests that connexin 26 is required for the maturation of certain cells in the cochlea. The GJB2 gene also plays a role in the growth and maturation of the outermost layer of skin (the epidermis).

What Conditions Are Related to the GJB2 Gene? Nonsyndromic Deafness - Caused by Mutations in the GJB2 Gene Researchers have identified more than 90 GJB2 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB1. DFNB1 deafness is inherited in an autosomal recessive manner, which means that two copies of the GJB2 gene in each cell are altered. GJB2 mutations probably alter gap junctions, which may disturb the level of potassium ions in the inner ear. Levels of potassium ions that are too high may affect the function and survival of cells that are needed for hearing. Other Disorders - Caused by Mutations in the GJB2 Gene Researchers have identified more than 90 GJB2 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB1. DFNB1 deafness is inherited in an autosomal recessive manner, which means that two copies of the GJB2 gene in each cell are altered. GJB2 mutations probably alter gap junctions, which may disturb the level of potassium ions in the inner ear. Levels of potassium ions that are too high may affect the function and survival of cells that are needed for hearing.

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Where Is the GJB2 Gene Located? Cytogenetic Location: 13q11-q12

Molecular Location on chromosome 13: base pairs 19,659,608 to 19,665,036 The GJB2 gene is located on the long (q) arm of chromosome 13 between positions 11 and 12.

References These sources were used to develop the Genetics Home Reference gene summary on the GJB2 gene. •


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Gerido DA, White TW. Connexin disorders of the ear, skin, and lens. Biochim Biophys Acta. 2004 Mar 23;1662(1-2):159-70. Review. PubMed citation

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Marlin S, Feldmann D, Blons H, Loundon N, Rouillon I, Albert S, Chauvin P, Garabedian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Lemarechal C, Dollfus H, Eliot MM, Delaunoy JL, David A, Calais C, Drouin-Garraud V, Obstoy MF, Goizet C, Duriez F, Fellmann F, Helias J, Vigneron J, Montaut B, Matin-Coignard D, Faivre L, Baumann C, Lewin P, Petit C, Denoyelle F. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg. 2005 Jun;131(6):481-7. PubMed citation

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OMIM: GJB2

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Sabag AD, Dagan O, Avraham KB. Connexins in hearing loss: a comprehensive overview. J Basic Clin Physiol Pharmacol. 2005;16(2-3):101-16. Review. PubMed citation

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Snoeckx RL, Hassan DM, Kamal NM, Van Den Bogaert K, Van Camp G. Mutation analysis of the GJB2 (connexin 26) gene in Egypt. Hum Mutat. 2005 Jul;26(1):60-1. PubMed citation

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Thonnissen E, Rabionet R, Arbones ML, Estivill X, Willecke K, Ott T. Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet. 2002 Aug;111(2):190-7. Epub 2002 Jun 22. PubMed citation

What Is the Official Name of the GJB6 Gene?16 The official name of this gene is “gap junction protein, beta 6 (connexin 30).” GJB6 is the gene's official symbol. The GJB6 gene is also known by other names, listed below.

What Is the Normal Function of the GJB6 Gene? The GJB6 gene provides instructions for making a protein called gap junction beta 6, more commonly known as connexin 30. Connexin 30 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells. The size of the gap junction and the types of particles that move through it are determined by the particular connexin proteins that make up the channel. Gap junctions made with connexin 30 transport potassium ions and certain small molecules. Connexin 30 is found in several different tissues throughout the body, including the brain, skin, and inner ear. Because of its presence in the inner ear, researchers are interested in this protein's role in hearing. Hearing requires the conversion of sound waves to electrical nerve impulses. This conversion involves many processes, including maintaining the proper level of potassium ions in the inner ear. Some studies indicate that gap junctions made with connexin 30 help to maintain the correct level of potassium ions. The GJB6 gene also plays a role in the growth and maturation of the outermost layer of skin (the epidermis).

What Conditions Are Related to the GJB6 Gene? Nonsyndromic Deafness - Caused by Mutations in the GJB6 Gene Researchers have identified a few GJB6 mutations in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB1. DFNB1 deafness is inherited in an autosomal recessive manner, which means that two copies of an altered gene in each cell are necessary to cause hearing loss. Some cases of DFNB1 deafness are caused by mutations that delete a large segment of DNA in both copies of the GJB6 gene. More commonly, however, a deletion occurs in one copy of the GJB6 gene, and a different mutation occurs in one copy of a neighboring gene called GJB2. Although the effect of a deletion in the GJB6 gene is unclear, 16

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=gjb6;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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it probably reduces the number of functional gap junctions. As a result, the proper level of potassium ions in the inner ear could be disturbed, disrupting the conversion of sound waves to nerve impulses. Other Disorders - Caused by Mutations in the GJB6 Gene Researchers have identified a few GJB6 mutations in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB1. DFNB1 deafness is inherited in an autosomal recessive manner, which means that two copies of an altered gene in each cell are necessary to cause hearing loss. Some cases of DFNB1 deafness are caused by mutations that delete a large segment of DNA in both copies of the GJB6 gene. More commonly, however, a deletion occurs in one copy of the GJB6 gene, and a different mutation occurs in one copy of a neighboring gene called GJB2. Although the effect of a deletion in the GJB6 gene is unclear, it probably reduces the number of functional gap junctions. As a result, the proper level of potassium ions in the inner ear could be disturbed, disrupting the conversion of sound waves to nerve impulses.

Where Is the GJB6 Gene Located? Cytogenetic Location: 13q12

Molecular Location on chromosome 13: base pairs 19,694,100 to 19,703,066 The GJB6 gene is located on the long (q) arm of chromosome 13 at position 12.


Common JE, Becker D, Di WL, Leigh IM, O'Toole EA, Kelsell DP. Functional studies of human skin disease- and deafness-associated connexin 30 mutations. Biochem Biophys Res Commun. 2002 Nov 15;298(5):651-6. PubMed citation

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del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Telleria D, Menendez I, Moreno F. A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med. 2002 Jan 24;346(4):243-9. PubMed citation

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Essenfelder GM, Bruzzone R, Lamartine J, Charollais A, Blanchet-Bardon C, Barbe MT, Meda P, Waksman G. Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. Hum Mol Genet. 2004 Aug 15;13(16):1703-14. Epub 2004 Jun 22. PubMed citation

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Marlin S, Feldmann D, Blons H, Loundon N, Rouillon I, Albert S, Chauvin P, Garabedian EN, Couderc R, Odent S, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Lemarechal C, Dollfus H, Eliot MM, Delaunoy JL, David A, Calais C, Drouin-Garraud V, Obstoy MF, Goizet C, Duriez F, Fellmann F, Helias J, Vigneron J, Montaut B, Matin-Coignard D, Faivre L, Baumann C, Lewin P, Petit C, Denoyelle F. GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients. Arch Otolaryngol Head Neck Surg. 2005 Jun;131(6):481-7. PubMed citation

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Rabionet R, Lopez-Bigas N, Arbones ML, Estivill X. Connexin mutations in hearing loss, dermatological and neurological disorders. Trends Mol Med. 2002 May;8(5):205-12. Review. PubMed citation

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What Is the Official Name of the KCNQ4 Gene?17 The official name of this gene is “potassium voltage-gated channel, KQT-like subfamily, member 4.” KCNQ4 is the gene's official symbol. The KCNQ4 gene is also known by other names, listed below.

What Is the Normal Function of the KCNQ4 Gene? The KCNQ4 gene provides instructions for making a protein called potassium voltage-gated channel KQT-like protein 4. The KCNQ4 protein is part of a protein family that forms channels to transport positively charged potassium atoms (potassium ions) between neighboring cells. The channels, made from four protein subunits, play a key role in the ability of cells to generate and transmit electrical signals. The specific function of a potassium channel depends on its protein components and its tissue location. Potassium channels made with the KCNQ4 protein are found in the inner ear and along part of the 17

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=kcnq4.

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nerve pathway from the ear to the brain (auditory pathway). KCNQ4 potassium channels are also found in small numbers in the heart and some muscles. Because KCNQ4 potassium channels are present in the inner ear and auditory pathway, researchers have focused on their role in hearing. Hearing requires the conversion of sound waves to electrical nerve signals. This conversion involves many processes, including maintaining the proper level of potassium ions in the inner ear. Although the exact role of KCNQ4 channels remains unknown, these channels appear to be critical for the efficient transmission of electrical nerve signals. KCNQ4 channels may help recycle potassium ions within the inner ear to maintain the proper potassium ion balance.

What Conditions Are Related to the KCNQ4 Gene? Nonsyndromic Deafness - Caused by Mutations in the KCNQ4 Gene Several KCNQ4 mutations have been reported in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA2. Most KCNQ4 mutations change one of the building blocks (amino acids) used to make the KCNQ4 protein. Nearly all of these changes affect the region of the protein that forms the pore or channel opening. As a result, the channel does not function properly and normal potassium ion levels may be disturbed. Two mutations delete part of the KCNQ4 gene, which results in an abnormally small KCNQ4 protein that cannot form functional channels. It is unclear whether deafness results from disturbed potassium levels within the inner ear, alterations in the auditory pathway, or both.

Where Is the KCNQ4 Gene Located? Cytogenetic Location: 1p34

Molecular Location on chromosome 1: base pairs 41,022,270 to 41,076,946 The KCNQ4 gene is located on the short (p) arm of chromosome 1 at position 34.

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References These sources were used to develop the Genetics Home Reference gene summary on the KCNQ4 gene. •

Coucke PJ, Van Hauwe P, Kelley PM, Kunst H, Schatteman I, Van Velzen D, Meyers J, Ensink RJ, Verstreken M, Declau F, Marres H, Kastury K, Bhasin S, McGuirt WT, Smith RJ, Cremers CW, Van de Heyning P, Willems PJ, Smith SD, Van Camp G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum Mol Genet. 1999 Jul;8(7):1321-8. PubMed citation

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Kamada F, Kure S, Kudo T, Suzuki Y, Oshima T, Ichinohe A, Kojima K, Niihori T, Kanno J, Narumi Y, Narisawa A, Kato K, Aoki Y, Ikeda K, Kobayashi T, Matsubara Y. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation. J Hum Genet. 2006;51(5):455-60. Epub 2006 Apr 5. PubMed citation

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Kubisch C, Schroeder BC, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell. 1999 Feb 5;96(3):437-46. PubMed citation

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OMIM

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Wangemann P. K(+) cycling and its regulation in the cochlea and the vestibular labyrinth. Audiol Neurootol. 2002 Jul-Aug;7(4):199-205. PubMed citation

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Willems PJ. Genetic causes of hearing loss. N Engl J Med. 2000 Apr 13;342(15):1101-9. Review. No abstract available. PubMed citation

What Is the Official Name of the LHFPL5 Gene?18 The official name of this gene is “lipoma HMGIC fusion partner-like 5.” LHFPL5 is the gene's official symbol. The LHFPL5 gene is also known by other names, listed below.

What Is the Normal Function of the LHFPL5 Gene? The LHFPL5 gene (also called TMHS) provides instructions for making a protein called LHFP-like protein 5. The specific role of this protein is unknown. Researchers suggest that LHFP-like protein 5 is important for the normal function of the inner ear and the hearing process. Hearing requires the conversion of sound waves to nerve impulses that are transmitted via the auditory nerve to the brain. LHFP-like protein 5 may play a role in this conversion process. Studies indicate that this protein may help in the formation of stereocilia, the hairlike structures that project from specialized cells called hair cells. 18

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=lhfpl5;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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Stereocilia line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses.

What Conditions Are Related to the LHFPL5 Gene? Nonsyndromic Deafness - Caused by Mutations in the LHFPL5 Gene Researchers have identified a few mutations in the LHFPL5 gene that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB67. Some of these mutations introduce a premature stop signal in the instructions for making LHFP-like protein 5. As a result, scientists believe that no protein is produced, or an abnormally small and nonfunctional protein is made. Other mutations replace one of the protein building blocks (amino acids) used to make LHFP-like protein 5 with an incorrect amino acid. It is unclear how LHFPL5 mutations cause hearing loss.

Where Is the LHFPL5 Gene Located? Cytogenetic Location: 6p21.31

Molecular Location on chromosome 6: base pairs 35,881,048 to 35,899,829 The LHFPL5 gene is located on the short (p) arm of chromosome 6 at position 21.31.

References These sources were used to develop the Genetics Home Reference gene summary on the LHFPL5 gene. •

Kalay E, Li Y, Uzumcu A, Uyguner O, Collin RW, Caylan R, Ulubil-Emiroglu M, Kersten FF, Hafiz G, van Wijk E, Kayserili H, Rohmann E, Wagenstaller J, Hoefsloot LH, Strom TM, Nurnberg G, Baserer N, den Hollander AI, Cremers FP, Cremers CW, Becker C, Brunner HG, Nurnberg P, Karaguzel A, Basaran S, Kubisch C, Kremer H, Wollnik B. Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. Hum Mutat. 2006 Jul;27(7):633-9. PubMed citation

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OMIM

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Shabbir MI, Ahmed ZM, Khan SY, Riazuddin S, Waryah AM, Khan SN, Camps RD, Ghosh M, Kabra M, Belyantseva IA, Friedman TB, Riazuddin S. Mutations of human TMHS cause recessively inherited non-syndromic hearing loss. J Med Genet. 2006 Aug;43(8):634-40. Epub 2006 Feb 3. PubMed citation

What Is the Official Name of the MT-TS1 Gene?19 The official name of this gene is “mitochondrially encoded tRNA serine 1 (UCN).” MT-TS1 is the gene's official symbol. The MT-TS1 gene is also known by other names, listed below.

What Is the Normal Function of the MT-TS1 Gene? The MT-TS1 gene provides instructions for making a particular type of RNA, a molecule that is a chemical cousin of DNA. This type of RNA, called transfer RNA (tRNA), helps assemble protein building blocks known as amino acids into full-length, functioning proteins. The MT-TS1 gene provides instructions for a specific form of transfer RNA that is designated as tRNASer(UCN). This molecule attaches to a particular amino acid, serine (Ser), and inserts it into the appropriate locations in many different proteins. The tRNASer(UCN) molecule is present only in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Through a process called oxidative phosphorylation, mitochondria use oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source. The tRNASer(UCN) molecule is involved in the assembly of proteins that carry out oxidative phosphorylation.

What Conditions Are Related to the MT-TS1 Gene? Nonsyndromic Deafness - Caused by Mutations in the MT-TS1 Gene At least four mutations in the MT-TS1 gene have been identified in several large families with hearing loss. In most cases, these mutations cause nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body). In some cases, however, these genetic changes are responsible for hearing loss associated with other health problems. Other Disorders - Caused by Mutations in the MT-TS1 Gene At least four mutations in the MT-TS1 gene have been identified in several large families with hearing loss. In most cases, these mutations cause nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body). In some cases, however, these genetic changes are responsible for hearing loss associated with other health problems. 19

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=mtts1.

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Where Is the MT-TS1 Gene Located? The MT-TS1 gene is located in mitochondrial DNA.

Molecular Location in mitochondrial DNA: base pairs 7,445 to 7,516 You and your healthcare professional may find the following resources about MT-TS1 helpful.

References These sources were used to develop the Genetics Home Reference gene summary on the MT-TS1 gene. •


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Gene Review: Nonsyndromic Hearing Loss and Deafness, Mitochondrial

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Grafakou O, Hol FA, Otfried Schwab K, Siers MH, ter Laak H, Trijbels F, Ensenauer R, Boelen C, Smeitink J. Exercise intolerance, muscle pain and lactic acidaemia associated with a 7497G>A mutation in the tRNASer(UCN) gene. J Inherit Metab Dis. 2003;26(6):593-600. PubMed citation

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Jaksch M, Klopstock T, Kurlemann G, Dorner M, Hofmann S, Kleinle S, Hegemann S, Weissert M, Muller-Hocker J, Pongratz D, Gerbitz KD. Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)) gene. Ann Neurol. 1998 Oct;44(4):635-40. PubMed citation

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Sevior KB, Hatamochi A, Stewart IA, Bykhovskaya Y, Allen-Powell DR, FischelGhodsian N, Maw MA. Mitochondrial A7445G mutation in two pedigrees with palmoplantar keratoderma and deafness. Am J Med Genet. 1998 Jan 13;75(2):179-85. PubMed citation

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Toompuu M, Yasukawa T, Suzuki T, Hakkinen T, Spelbrink JN, Watanabe K, Jacobs HT. The 7472insC mitochondrial DNA mutation impairs the synthesis and extent of aminoacylation of tRNASer(UCN) but not its structure or rate of turnover. J Biol Chem. 2002 Jun 21;277(25):22240-50. Epub 2002 Mar 27. PubMed citation

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What Is the Official Name of the MYO15A Gene?20 The official name of this gene is “myosin XVA.” MYO15A is the gene's official symbol. The MYO15A gene is also known by other names, listed below.

What Is the Normal Function of the MYO15A Gene? The MYO15A gene provides instructions for making a protein called myosin XVA, which is part of a group of proteins called unconventional myosins. These proteins, which have similar structures, each play a role in transporting molecules within cells. Myosins interact with actin, a protein that is important for cell movement and shape. Researchers believe that myosins use long filaments of actin as tracks along which to transport other molecules. Myosin XVA is made in the inner ear, the pituitary gland (a structure at the base of the brain that makes several hormones), and other tissues. It appears to be essential for normal hearing. In the inner ear, myosin XVA plays a role in the development and maintenance of hairlike projections called stereocilia. Stereocilia, which are rich in actin, line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses. One function of myosin XVA is to carry a protein called whirlin to its normal location at the tips of stereocilia. Both proteins are essential for building these structures.

20

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=myo15a;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Conditions Are Related to the MYO15A Gene? Nonsyndromic Deafness - Caused by Mutations in the MYO15A Gene At least seven mutations in the MYO15A gene have been identified in families with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB3. Most of these genetic changes alter a single protein building block (amino acid) in critical regions of the myosin XVA protein. MYO15A mutations disrupt the usual function of myosin XVA or cause an abnormally short, nonfunctional version of the protein to be made. Altering the function of myosin XVA disrupts the structure and organization of stereocilia, leading to hearing loss.

Where Is the MYO15A Gene Located? Cytogenetic Location: 17p11.2

Molecular Location on chromosome 17: base pairs 17,952,744 to 18,023,840 The MYO15A gene is located on the short (p) arm of chromosome 17 at position 11.2.

References These sources were used to develop the Genetics Home Reference gene summary on the MYO15A gene. •

Anderson DW, Probst FJ, Belyantseva IA, Fridell RA, Beyer L, Martin DM, Wu D, Kachar B, Friedman TB, Raphael Y, Camper SA. The motor and tail regions of myosin XV are critical for normal structure and function of auditory and vestibular hair cells. Hum Mol Genet. 2000 Jul 22;9(12):1729-38. PubMed citation

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Belyantseva IA, Boger ET, Friedman TB. Myosin XVa localizes to the tips of inner ear sensory cell stereocilia and is essential for staircase formation of the hair bundle. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13958-63. Epub 2003 Nov 10. PubMed citation

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Delprat B, Michel V, Goodyear R, Yamasaki Y, Michalski N, El-Amraoui A, Perfettini I, Legrain P, Richardson G, Hardelin JP, Petit C. Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and

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interact directly. Hum Mol Genet. 2005 Feb 1;14(3):401-10. Epub 2004 Dec 8. PubMed citation •

Liburd N, Ghosh M, Riazuddin S, Naz S, Khan S, Ahmed Z, Riazuddin S, Liang Y, Menon PS, Smith T, Smith AC, Chen KS, Lupski JR, Wilcox ER, Potocki L, Friedman TB. Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum Genet. 2001 Nov;109(5):535-41. Epub 2001 Oct 03. PubMed citation

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Lin HW, Schneider ME, Kachar B. When size matters: the dynamic regulation of stereocilia lengths. Curr Opin Cell Biol. 2005 Feb;17(1):55-61. Review. PubMed citation

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Lloyd RV, Vidal S, Jin L, Zhang S, Kovacs K, Horvath E, Scheithauer BW, Boger ET, Fridell RA, Friedman TB. Myosin XVA expression in the pituitary and in other neuroendocrine tissues and tumors. Am J Pathol. 2001 Oct;159(4):1375-82. PubMed citation

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Steel KP, Brown SD. More deafness genes. Science. 1998 May 29;280(5368):1403. No abstract available. PubMed citation

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Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, Morton CC, Morell RJ, Noben-Trauth K, Camper SA, Friedman TB. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science. 1998 May 29;280(5368):1447-51. PubMed citation

What Is the Official Name of the MYO6 Gene?21 The official name of this gene is “myosin VI.” MYO6 is the gene's official symbol. The MYO6 gene is also known by other names, listed below.

What Is the Normal Function of the MYO6 Gene? The MYO6 gene provides instructions for making a protein called myosin VI, which is part of a group of proteins called unconventional myosins. These proteins, which have similar structures, each play a role in transporting molecules within cells. Myosins interact with actin, a protein that is important for cell movement and shape. Researchers believe that myosins use long filaments of actin as tracks along which to transport other molecules. Myosin VI is produced in the inner ear as well as in many other cell types. In the inner ear, myosin VI plays a role in the development and maintenance of hairlike projections called stereocilia. Stereocilia, which are rich in actin, line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses, which is an essential process for normal hearing.

21

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=myo6.

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What Conditions Are Related to the MYO6 Gene? Nonsyndromic Deafness - Caused by Mutations in the MYO6 Gene At least three mutations in the MYO6 gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB37. These mutations cause an autosomal recessive form of nonsyndromic deafness. Autosomal recessive inheritance means that two copies of the gene in each cell are altered. Some of these mutations lead to changes in single amino acids (the building blocks of proteins) in the myosin VI protein. Other mutations cause the cell to produce an abnormally short version of myosin VI. MYO6 mutations probably alter the function of myosin VI, which disrupts the structure and organization of stereocilia and leads to hearing loss.

Where Is the MYO6 Gene Located? Cytogenetic Location: 6q13

Molecular Location on chromosome 6: base pairs 76,515,702 to 76,682,664 The MYO6 gene is located on the long (q) arm of chromosome 6 at position 13.

References These sources were used to develop the Genetics Home Reference gene summary on the MYO6 gene. •

Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, Mohiddin SA, Fananapazir L, Caruso RC, Husnain T, Khan SN, Riazuddin S, Griffith AJ, Friedman TB, Wilcox ER. Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hum Genet. 2003 May;72(5):1315-22. Epub 2003 Apr 08. PubMed citation

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Breckler J, Au K, Cheng J, Hasson T, Burnside B. Novel myosin VI isoform is abundantly expressed in retina. Exp Eye Res. 2000 Jan;70(1):121-34. PubMed citation

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Cramer LP. Myosin VI: roles for a minus end-directed actin motor in cells. J Cell Biol. 2000 Sep 18;150(6):F121-6. Review. No abstract available. PubMed citation

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Hasson T. Myosin VI: two distinct roles in endocytosis. J Cell Sci. 2003 Sep 1;116(Pt 17):3453-61. PubMed citation

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Melchionda S, Ahituv N, Bisceglia L, Sobe T, Glaser F, Rabionet R, Arbones ML, Notarangelo A, Di Iorio E, Carella M, Zelante L, Estivill X, Avraham KB, Gasparini P. MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. Am J Hum Genet. 2001 Sep;69(3):635-40. Epub 2001 Jul 20. PubMed citation

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Mohiddin SA, Ahmed ZM, Griffith AJ, Tripodi D, Friedman TB, Fananapazir L, Morell RJ. Novel association of hypertrophic cardiomyopathy, sensorineural deafness, and a mutation in unconventional myosin VI (MYO6). J Med Genet. 2004 Apr;41(4):309-14. No abstract available. PubMed citation

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OMIM

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Wells AL, Lin AW, Chen LQ, Safer D, Cain SM, Hasson T, Carragher BO, Milligan RA, Sweeney HL. Myosin VI is an actin-based motor that moves backwards. Nature. 1999 Sep 30;401(6752):505-8. PubMed citation

What Is the Official Name of the MYO7A Gene?22 The official name of this gene is “myosin VIIA.” MYO7A is the gene's official symbol. The MYO7A gene is also known by other names, listed below.

What Is the Normal Function of the MYO7A Gene? The MYO7A gene provides instructions for making a protein called myosin VIIA, which is part of a group of proteins called unconventional myosins. These proteins, which have similar structures, each play a role in transporting molecules within cells. Myosins interact with actin, a protein that is important for cell movement and shape. Researchers believe that myosins use long filaments of actin as tracks along which to transport other molecules. Myosin VIIA is made primarily in the inner ear and the light-sensitive tissue at the back of the eye (the retina). In the inner ear, myosin VIIA plays a role in the development and maintenance of hairlike projections called stereocilia. Stereocilia, which are rich in actin, line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses. Myosin VIIA is also found in the pigmented cells of the retina (the retinal pigment epithelium or RPE), and probably plays a similar role in the development and maintenance

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of this tissue. Research suggests that one function of myosin VIIA is to carry small sacs of pigment called melanosomes within the retinal pigment epithelium.

What Conditions Are Related to the MYO7A Gene? Nonsyndromic Deafness - Caused by Mutations in the MYO7A Gene At least eight mutations in the MYO7A gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB2. These mutations cause an autosomal recessive form of nonsyndromic deafness. Autosomal recessive inheritance means that two copies of the gene in each cell are altered. Most of these genetic changes alter single protein building blocks (amino acids) in critical regions of the myosin VIIA protein. These changes impair the normal function of myosin VIIA. A loss of normal myosin VIIA function likely disrupts the development, structure, and organization of stereocilia, leading to hearing loss. Usher Syndrome - Caused by Mutations in the MYO7A Gene At least eight mutations in the MYO7A gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB2. These mutations cause an autosomal recessive form of nonsyndromic deafness. Autosomal recessive inheritance means that two copies of the gene in each cell are altered. Most of these genetic changes alter single protein building blocks (amino acids) in critical regions of the myosin VIIA protein. These changes impair the normal function of myosin VIIA. A loss of normal myosin VIIA function likely disrupts the development, structure, and organization of stereocilia, leading to hearing loss.

Where Is the MYO7A Gene Located? Cytogenetic Location: 11q13.5

Molecular Location on chromosome 11: base pairs 76,516,957 to 76,603,930 The MYO7A gene is located on the long (q) arm of chromosome 11 at position 13.5.

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Adato A, Kalinski H, Weil D, Chaib H, Korostishevsky M, Bonne-Tamir B. Possible interaction between USH1B and USH3 gene products as implied by apparent digenic deafness inheritance. Am J Hum Genet. 1999 Jul;65(1):261-5. No abstract available. PubMed citation

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Adato A, Michel V, Kikkawa Y, Reiners J, Alagramam KN, Weil D, Yonekawa H, Wolfrum U, El-Amraoui A, Petit C. Interactions in the network of Usher syndrome type 1 proteins. Hum Mol Genet. 2005 Feb 1;14(3):347-56. Epub 2004 Dec 8. PubMed citation

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Bharadwaj AK, Kasztejna JP, Huq S, Berson EL, Dryja TP. Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I. Exp Eye Res. 2000 Aug;71(2):173-81. PubMed citation

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Bolz H, Bolz SS, Schade G, Kothe C, Mohrmann G, Hess M, Gal A. Impaired calmodulin binding of myosin-7A causes autosomal dominant hearing loss (DFNA11). Hum Mutat. 2004 Sep;24(3):274-5. PubMed citation

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El-Amraoui A, Petit C. Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells. J Cell Sci. 2005 Oct 15;118(Pt 20):4593-603. Review. PubMed citation

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Entrez Gene

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Gibbs D, Kitamoto J, Williams DS. Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6481-6. Epub 2003 May 12. PubMed citation

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Hasson T, Heintzelman MB, Santos-Sacchi J, Corey DP, Mooseker MS. Expression in cochlea and retina of myosin VIIa, the gene product defective in Usher syndrome type 1B. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9815-9. PubMed citation

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Liu XZ, Walsh J, Mburu P, Kendrick-Jones J, Cope MJ, Steel KP, Brown SD. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat Genet. 1997 Jun;16(2):188-90. PubMed citation

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OMIM: MYO7A

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Petit C. Memorial lecture-hereditary sensory defects: from genes to pathogenesis. Am J Med Genet A. 2004 Sep 15;130(1):3-7. No abstract available. PubMed citation

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Petit C. Usher syndrome: from genetics to pathogenesis. Annu Rev Genomics Hum Genet. 2001;2:271-97. Review. PubMed citation

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Tamagawa Y, Ishikawa K, Ishikawa K, Ishida T, Kitamura K, Makino S, Tsuru T, Ichimura K. Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation. Laryngoscope. 2002 Feb;112(2):292-7. PubMed citation

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Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F, Walsh J, Mburu P, Varela A, Levilliers J, Weston MD, et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature. 1995 Mar 2;374(6517):60-1. PubMed citation

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Weil D, Kussel P, Blanchard S, Levy G, Levi-Acobas F, Drira M, Ayadi H, Petit C. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat Genet. 1997 Jun;16(2):191-3. PubMed citation

What Is the Official Name of the OTOF Gene?23 The official name of this gene is “otoferlin.” OTOF is the gene's official symbol. The OTOF gene is also known by other names, listed below.

What Is the Normal Function of the OTOF Gene? The OTOF gene provides instructions for making a protein called otoferlin. This protein is present in the brain and the cochlea, which is a snail-shaped structure in the inner ear that helps process sound. Although the exact function of otoferlin is uncertain, it appears to be essential for normal hearing. Researchers believe that otoferlin may play a role in releasing chemical signals (neurotransmitters) from nerve cells that are involved in hearing. This process is dependent on the concentration of calcium within the cell. The otoferlin protein has several regions called C2 domains that bind to calcium and use it to interact with other molecules.

What Conditions Are Related to the OTOF Gene? Nonsyndromic Deafness - Caused by Mutations in the OTOF Gene At least 16 mutations in the OTOF gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other 23

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=otof.

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parts of the body) called DFNB9. People with these mutations have a type of hearing loss called auditory neuropathy, which occurs when sound is not transmitted properly from the inner ear to the brain.

Where Is the OTOF Gene Located? Cytogenetic Location: 2p23.1

Molecular Location on chromosome 2: base pairs 26,533,574 to 26,635,069 The OTOF gene is located on the short (p) arm of chromosome 2 at position 23.1.

References These sources were used to develop the Genetics Home Reference gene summary on the OTOF gene. •

Migliosi V, Modamio-Hoybjor S, Moreno-Pelayo MA, Rodriguez-Ballesteros M, Villamar M, Telleria D, Menendez I, Moreno F, Del Castillo I. Q829X, a novel mutation in the gene encoding otoferlin (OTOF), is frequently found in Spanish patients with prelingual non-syndromic hearing loss. J Med Genet. 2002 Jul;39(7):502-6. No abstract available. PubMed citation

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Mirghomizadeh F, Pfister M, Apaydin F, Petit C, Kupka S, Pusch CM, Zenner HP, Blin N. Substitutions in the conserved C2C domain of otoferlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness. Neurobiol Dis. 2002 Jul;10(2):157-64. PubMed citation

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Rodriguez-Ballesteros M, del Castillo FJ, Martin Y, Moreno-Pelayo MA, Morera C, Prieto F, Marco J, Morant A, Gallo-Teran J, Morales-Angulo C, Navas C, Trinidad G, Tapia MC, Moreno F, del Castillo I. Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF). Hum Mutat. 2003 Dec;22(6):451-6. PubMed citation

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Tekin M, Akcayoz D, Incesulu A. A novel missense mutation in a C2 domain of OTOF results in autosomal recessive auditory neuropathy. Am J Med Genet A. 2005 Sep 15;138(1):6-10. PubMed citation

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Varga R, Avenarius MR, Kelley PM, Keats BJ, Berlin CI, Hood LJ, Morlet TG, Brashears SM, Starr A, Cohn ES, Smith RJ, Kimberling WJ. OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory

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neuropathy allele. J Med Genet. 2006 Jul;43(7):576-81. Epub 2005 Dec 21. PubMed citation •

Varga R, Kelley PM, Keats BJ, Starr A, Leal SM, Cohn E, Kimberling WJ. Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene. J Med Genet. 2003 Jan;40(1):45-50. No abstract available. PubMed citation

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Yasunaga S, Grati M, Chardenoux S, Smith TN, Friedman TB, Lalwani AK, Wilcox ER, Petit C. OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9. Am J Hum Genet. 2000 Sep;67(3):591-600. Epub 2000 Jul 19. PubMed citation

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Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C. A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet. 1999 Apr;21(4):363-9. PubMed citation

What Is the Official Name of the PCDH15 Gene?24 The official name of this gene is “protocadherin 15.” PCDH15 is the gene's official symbol. The PCDH15 gene is also known by other names, listed below.

What Is the Normal Function of the PCDH15 Gene? The PCDH15 gene provides instructions for making a protein called protocadherin 15, a type of protein that helps cells stick together. Protocadherin 15 is made in the inner ear and in specialized cells in the eye that detect light and color (retinal photoreceptors), as well as in other tissues. This protein interacts with other proteins in the cell membrane to carry out its normal role in cell attachment. In the inner ear, protocadherin 15 probably plays a role in the development and maintenance of the hairlike projections (stereocilia) that line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses, which is an essential process for normal hearing. The exact function of protocadherin 15 in the retina has not been determined, but it probably plays a role in the development and maintenance of specialized photoreceptor cells that detect light and color.

24

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=pcdh15;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Conditions Are Related to the PCDH15 Gene? Nonsyndromic Deafness - Caused by Mutations in the PCDH15 Gene Researchers have identified a few mutations in the PCDH15 gene that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB23. These mutations lead to changes in single protein building blocks (amino acids) in the protocadherin 15 protein, which alters its normal structure and function. Deafness most likely results because of improper development of the stereocilia in the inner ear. Usher Syndrome - Caused by Mutations in the PCDH15 Gene Researchers have identified a few mutations in the PCDH15 gene that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB23. These mutations lead to changes in single protein building blocks (amino acids) in the protocadherin 15 protein, which alters its normal structure and function. Deafness most likely results because of improper development of the stereocilia in the inner ear.

Where Is the PCDH15 Gene Located? Cytogenetic Location: 10q21.1

Molecular Location on chromosome 10: base pairs 55,250,865 to 56,231,056 The PCDH15 gene is located on the long (q) arm of chromosome 10 at position 21.1.

References These sources were used to develop the Genetics Home Reference gene summary on the PCDH15 gene. •

Ahmed ZM, Goodyear R, Riazuddin S, Lagziel A, Legan PK, Behra M, Burgess SM, Lilley KS, Wilcox ER, Riazuddin S, Griffith AJ, Frolenkov GI, Belyantseva IA, Richardson GP, Friedman TB. The tip-link antigen, a protein associated with the

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transduction complex of sensory hair cells, is protocadherin-15. J Neurosci. 2006 Jun 28;26(26):7022-34. PubMed citation •

Ahmed ZM, Riazuddin S, Ahmad J, Bernstein SL, Guo Y, Sabar MF, Sieving P, Riazuddin S, Griffith AJ, Friedman TB, Belyantseva IA, Wilcox ER. PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum Mol Genet. 2003 Dec 15;12(24):3215-23. Epub 2003 Oct 21. PubMed citation

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Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, Morell RJ, Friedman TB, Riazuddin S, Wilcox ER. Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am J Hum Genet. 2001 Jul;69(1):25-34. Epub 2001 Jun 07. PubMed citation

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Alagramam KN, Yuan H, Kuehn MH, Murcia CL, Wayne S, Srisailpathy CR, Lowry RB, Knaus R, Van Laer L, Bernier FP, Schwartz S, Lee C, Morton CC, Mullins RF, Ramesh A, Van Camp G, Hageman GS, Woychik RP, Smith RJ, Hagemen GS. Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum Mol Genet. 2001 Aug 1;10(16):1709-18. Erratum in: Hum Mol Genet 2001 Oct 15;10(22):2603. PubMed citation

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Ben-Yosef T, Ness SL, Madeo AC, Bar-Lev A, Wolfman JH, Ahmed ZM, Desnick RJ, Willner JP, Avraham KB, Ostrer H, Oddoux C, Griffith AJ, Friedman TB. A mutation of PCDH15 among Ashkenazi Jews with the type 1 Usher syndrome. N Engl J Med. 2003 Apr 24;348(17):1664-70. No abstract available. PubMed citation

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Brownstein Z, Ben-Yosef T, Dagan O, Frydman M, Abeliovich D, Sagi M, Abraham FA, Taitelbaum-Swead R, Shohat M, Hildesheimer M, Friedman TB, Avraham KB. The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa. Pediatr Res. 2004 Jun;55(6):995-1000. Epub 2004 Mar 17. PubMed citation

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Reiners J, Marker T, Jurgens K, Reidel B, Wolfrum U. Photoreceptor expression of the Usher syndrome type 1 protein protocadherin 15 (USH1F) and its interaction with the scaffold protein harmonin (USH1C). Mol Vis. 2005 May 12;11:347-55. PubMed citation

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Senften M, Schwander M, Kazmierczak P, Lillo C, Shin JB, Hasson T, Geleoc GS, Gillespie PG, Williams D, Holt JR, Muller U. Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells. J Neurosci. 2006 Feb 15;26(7):2060-71. PubMed citation

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What Is the Official Name of the POU3F4 Gene?25 The official name of this gene is “POU domain, class 3, transcription factor 4.” POU3F4 is the gene's official symbol. The POU3F4 gene is also known by other names, listed below.

What Is the Normal Function of the POU3F4 Gene? The POU3F4 gene provides instructions for making a protein that helps regulate the activity of other genes. Based on this role, the protein is called a transcription factor. The POU3F4 gene is part of a larger family of genes called POU domain genes, all of which produce transcription factors. POU domain genes play a role in determining cell types in the central nervous system during early development. Each protein in the POU domain family has two regions, called the POU-specific domain and POU homeodomain, that bind to the DNA of other genes. The POU3F4 gene is likely to be involved in the development of the middle and inner ear, and is also active in certain regions of the brain before birth. Researchers have not determined which genes are regulated by the POU3F4 protein.

What Conditions Are Related to the POU3F4 Gene? Nonsyndromic Deafness - Caused by Mutations in the POU3F4 Gene Mutations in or near the POU3F4 gene cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFN3. This form of hearing loss usually involves abnormalities of both the inner and middle ear (mixed hearing loss). People who have surgery for this form of deafness are at high risk of a complication called a perilymphatic gusher. This complication causes a leakage of fluid from the inner ear that can result in severe dizziness and a total loss of hearing.

Where Is the POU3F4 Gene Located? Cytogenetic Location: Xq21.1

25

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=pou3f4.

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Molecular Location on the X chromosome: base pairs 82,649,956 to 82,651,430 The POU3F4 gene is located on the long (q) arm of the X chromosome at position 21.1.

References These sources were used to develop the Genetics Home Reference gene summary on the POU3F4 gene. •

Bitner-Glindzicz M, Turnpenny P, Hoglund P, Kaariainen H, Sankila EM, van der Maarel SM, de Kok YJ, Ropers HH, Cremers FP, Pembrey M, et al. Further mutations in Brain 4 (POU3F4) clarify the phenotype in the X-linked deafness, DFN3. Hum Mol Genet. 1995 Aug;4(8):1467-9. No abstract available. PubMed citation

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Cremers CW, Snik AF, Huygen PL, Joosten FB, Cremers FP. X-linked mixed deafness syndrome with congenital fixation of the stapedial footplate and perilymphatic gusher (DFN3). Adv Otorhinolaryngol. 2002;61:161-7. No abstract available. PubMed citation

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de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, Huber I, Monaco AP, Malcolm S, Pembrey ME, Ropers HH, Cremers FP. Association between X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science. 1995 Feb 3;267(5198):685-8. PubMed citation

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Friedman RA, Bykhovskaya Y, Tu G, Talbot JM, Wilson DF, Parnes LS, FischelGhodsian N. Molecular analysis of the POU3F4 gene in patients with clinical and radiographic evidence of X-linked mixed deafness with perilymphatic gusher. Ann Otol Rhinol Laryngol. 1997 Apr;106(4):320-5. PubMed citation

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Vore AP, Chang EH, Hoppe JE, Butler MG, Forrester S, Schneider MC, Smith LL, Burke DW, Campbell CA, Smith RJ. Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness. Arch Otolaryngol Head Neck Surg. 2005 Dec;131(12):1057-63. PubMed citation

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Wang QJ, Li QZ, Rao SQ, Zhao YL, Yuan H, Yang WY, Han DY, Shen Y. A novel mutation of POU3F4 causes congenital profound sensorineural hearing loss in a large Chinese family. Laryngoscope. 2006 Jun;116(6):944-50. PubMed citation

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What Is the Official Name of the SLC26A4 Gene?26 The official name of this gene is “solute carrier family 26, member 4.” SLC26A4 is the gene's official symbol. The SLC26A4 gene is also known by other names, listed below.

What Is the Normal Function of the SLC26A4 Gene? The SLC26A4 gene provides instructions for making a protein called pendrin. This protein transports negatively charged particles across cell membranes. Pendrin is present in the kidneys, inner ear, and thyroid. The thyroid is a butterfly-shaped tissue at the base of the neck that releases hormones to help regulate growth and the rate of chemical reactions in the body. Although the exact function of pendrin is not fully understood, researchers have suggested particular roles for pendrin in various tissues. In the thyroid, pendrin probably transports negatively charged iodine atoms (iodide ions) out of cells. Iodide ions bind to a protein called thyroglobulin, which is an important step in the production of thyroid hormones. In the kidneys, pendrin probably helps regulate acidity by transporting negatively charged particles, called bicarbonate ions, into the urine. Pendrin's likely role in the inner ear is to help control the proper balance of charged particles. Maintaining the correct level of charged particles is important for supporting reactions that are critical to the hearing process and for determining the amount of fluid that bathes the inner ear. The fluid level appears to be particularly important during development of the inner ear, as it may influence the shape of the bony structures such as the cochlea and vestibular aqueduct. The cochlea is a snailshaped structure that helps process sound. The vestibular aqueduct is a bony canal that connects the inner ear with a cavity in the brain.

What Conditions Are Related to the SLC26A4 Gene? Nonsyndromic Deafness - Caused by Mutations in the SLC26A4 Gene Researchers have identified at least 40 SLC26A4 mutations in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB4. People with DFNB4 deafness usually have an enlarged vestibular aqueduct. Pendred Syndrome - Caused by Mutations in the SLC26A4 Gene Researchers have identified at least 40 SLC26A4 mutations in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB4. People with DFNB4 deafness usually have an enlarged vestibular aqueduct.

26

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=slc26a4;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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Where Is the SLC26A4 Gene Located? Cytogenetic Location: 7q31

Molecular Location on chromosome 7: base pairs 107,088,315 to 107,145,489 The SLC26A4 gene is located on the long (q) arm of chromosome 7 at position 31.

References These sources were used to develop the Genetics Home Reference gene summary on the SLC26A4 gene. •

Albert S, Blons H, Jonard L, Feldmann D, Chauvin P, Loundon N, Sergent-Allaoui A, Houang M, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Dollfus H, Eliot MM, David A, Calais C, Drouin-Garraud V, Obstoy MF, Tran Ba Huy P, Lacombe D, Duriez F, Francannet C, Bitoun P, Petit C, Garabedian EN, Couderc R, Marlin S, Denoyelle F. SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. Eur J Hum Genet. 2006 Jun;14(6):773-9. PubMed citation

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Blons H, Feldmann D, Duval V, Messaz O, Denoyelle F, Loundon N, Sergout-Allaoui A, Houang M, Duriez F, Lacombe D, Delobel B, Leman J, Catros H, Journel H, DrouinGarraud V, Obstoy MF, Toutain A, Oden S, Toublanc JE, Couderc R, Petit C, Garabedian EN, Marlin S. Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity. Clin Genet. 2004 Oct;66(4):333-40. PubMed citation

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Campbell C, Cucci RA, Prasad S, Green GE, Edeal JB, Galer CE, Karniski LP, Sheffield VC, Smith RJ. Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations. Hum Mutat. 2001 May;17(5):403-11. PubMed citation

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Dawson PA, Markovich D. Pathogenetics of the human SLC26 transporters. Curr Med Chem. 2005;12(4):385-96. Review. PubMed citation

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Gene Review: Pendred Syndrome

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Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, Wilcox ER. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet. 1998 Mar;18(3):215-7. No abstract available. PubMed citation

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Pryor SP, Madeo AC, Reynolds JC, Sarlis NJ, Arnos KS, Nance WE, Yang Y, Zalewski CK, Brewer CC, Butman JA, Griffith AJ. SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities. J Med Genet. 2005 Feb;42(2):159-65. No abstract available. PubMed citation

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Scott DA, Wang R, Kreman TM, Sheffield VC, Karniski LP. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet. 1999 Apr;21(4):440-3. PubMed citation

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Wu CC, Chen PJ, Hsu CJ. Specificity of SLC26A4 mutations in the pathogenesis of inner ear malformations. Audiol Neurootol. 2005 Jul-Aug;10(4):234-42. Epub 2005 May 18. PubMed citation

What Is the Official Name of the STRC Gene?27 The official name of this gene is “stereocilin.” STRC is the gene's official symbol. The STRC gene is also known by other names, listed below.

What Is the Normal Function of the STRC Gene? The STRC gene provides instructions for making a protein called stereocilin. Researchers are interested in stereocilin's role in hearing because of its presence in the inner ear. Hearing requires the conversion of sound waves to nerve impulses that are transmitted via the auditory nerve to the brain. Stereocilin may play a role in this conversion process. Studies indicate that stereocilin is associated with hairlike structures called stereocilia. Stereocilia project from specialized cells called hair cells and bend in response to sound waves. This bending motion triggers a series of reactions that generate a nerve impulse. Although the exact function of the stereocilin protein is unknown, it appears to be important for normal hearing.

What Conditions Are Related to the STRC Gene? Nonsyndromic Deafness - Caused by Mutations in the STRC Gene Researchers have identified a few STRC mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB16. These mutations add a small amount of DNA to the STRC gene or delete DNA from the gene. These changes probably result in an abnormal version of stereocilin. The abnormal stereocilin protein could impair the function of stereocilia, leading to hearing loss.

27

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=strc.

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Where Is the STRC Gene Located? Cytogenetic Location: 15q15.3

Molecular Location on chromosome 15: base pairs 41,679,052 to 41,698,289 The STRC gene is located on the long (q) arm of chromosome 15 at position 15.3.

References These sources were used to develop the Genetics Home Reference gene summary on the STRC gene. •

OMIM

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Verpy E, Masmoudi S, Zwaenepoel I, Leibovici M, Hutchin TP, Del Castillo I, Nouaille S, Blanchard S, Laine S, Popot JL, Moreno F, Mueller RF, Petit C. Mutations in a new gene encoding a protein of the hair bundle cause non-syndromic deafness at the DFNB16 locus. Nat Genet. 2001 Nov;29(3):345-9. PubMed citation

What Is the Official Name of the TECTA Gene?28 The official name of this gene is “tectorin alpha.” TECTA is the gene's official symbol. The TECTA gene is also known by other names, listed below.

28

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=tecta;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Is the Normal Function of the TECTA Gene? The TECTA gene provides instructions for making a protein called alpha-tectorin. This protein is found in the inner ear, as part of a structure called the tectorial membrane. The tectorial membrane helps to convert sound waves to nerve impulses, a critical process for normal hearing. Alpha-tectorin interacts with other proteins to form the tectorial membrane. Two regions of the alpha-tectorin protein, called the vWFD domain and the zona pellucida domain, are important for protein interactions and assembly of the tectorial membrane.

What Conditions Are Related to the TECTA Gene? Nonsyndromic Deafness - Caused by Mutations in the TECTA Gene Researchers have identified several TECTA mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA8/A12. DFNA8/A12 deafness is inherited in an autosomal dominant manner, which means that one copy of an altered TECTA gene in each cell is sufficient to cause hearing loss. TECTA mutations replace one of the protein building blocks (amino acids) used to make alpha-tectorin with an incorrect amino acid. TECTA mutations affect the vWFD domain or the zona pellucida domain, which are important regions for interactions with other proteins. If the amino acid replacement alters normal protein interactions, it could disrupt the structure of the tectorial membrane and the conversion of sound to nerve impulses.

Where Is the TECTA Gene Located? Cytogenetic Location: 11q22-q24

Molecular Location on chromosome 11: base pairs 120,478,584 to 120,566,724 The TECTA gene is located on the long (q) arm of chromosome 11 between positions 22 and 24.

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References These sources were used to develop the Genetics Home Reference gene summary on the TECTA gene. •

Balciuniene J, Dahl N, Jalonen P, Verhoeven K, Van Camp G, Borg E, Pettersson U, Jazin EE. Alpha-tectorin involvement in hearing disabilities: one gene--two phenotypes. Hum Genet. 1999 Sep;105(3):211-6. PubMed citation

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Moreno-Pelayo MA, del Castillo I, Villamar M, Romero L, Hernandez-Calvin FJ, Herraiz C, Barbera R, Navas C, Moreno F. A cysteine substitution in the zona pellucida domain of alpha-tectorin results in autosomal dominant, postlingual, progressive, mid frequency hearing loss in a Spanish family. J Med Genet. 2001 May;38(5):E13. No abstract available. PubMed citation

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Naz S, Alasti F, Mowjoodi A, Riazuddin S, Sanati MH, Friedman TB, Griffith AJ, Wilcox ER, Riazuddin S. Distinctive audiometric profile associated with DFNB21 alleles of TECTA. J Med Genet. 2003 May;40(5):360-3. No abstract available. PubMed citation

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OMIM

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Pfister M, Thiele H, Van Camp G, Fransen E, Apaydin F, Aydin O, Leistenschneider P, Devoto M, Zenner HP, Blin N, Nurnberg P, Ozkarakas H, Kupka S. A genotypephenotype correlation with gender-effect for hearing impairment caused by TECTA mutations. Cell Physiol Biochem. 2004;14(4-6):369-76. PubMed citation

What Is the Official Name of the TMC1 Gene?29 The official name of this gene is “transmembrane channel-like 1.” TMC1 is the gene's official symbol. The TMC1 gene is also known by other names, listed below.

What Is the Normal Function of the TMC1 Gene? The TMC1 gene provides instructions for making a protein called transmembrane channellike 1. This protein is found in the inner ear, but its function is not fully understood. Based on its location in the inner ear, the TMC1 protein probably plays a role in converting sound waves to nerve impulses, a critical process for normal hearing. Alternatively, the TMC1 protein may be involved in signalling processes that are important for the survival of cells in the inner ear.

29

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=tmc1.

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What Conditions Are Related to the TMC1 Gene? Nonsyndromic Deafness - Caused by Mutations in the TMC1 Gene Researchers have identified several TMC1 mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB7/B11. This form of deafness is inherited in an autosomal recessive manner, which means that two copies of the TMC1 gene in each cell are altered. Some TMC1 mutations create a premature stop signal in the instructions for making the TMC1 protein. As a result, researchers believe that no protein is produced or an abnormally small protein is made. Other mutations delete part of the TMC1 gene. A few mutations replace one of the building blocks (amino acids) used to make the TMC1 protein with an incorrect amino acid. This type of mutation may alter the 3-dimensional shape of the TMC1 protein. TMC1 mutations that cause autosomal recessive deafness probably affect the normal activity of the TMC1 protein and disrupt the conversion of sound waves to nerve impulses.

Where Is the TMC1 Gene Located? Cytogenetic Location: 9q21.12

Molecular Location on chromosome 9: base pairs 74,326,536 to 74,641,086 The TMC1 gene is located on the long (q) arm of chromosome 9 at position 21.12.

References These sources were used to develop the Genetics Home Reference gene summary on the TMC1 gene. •


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Kalay E, Karaguzel A, Caylan R, Heister A, Cremers FP, Cremers CW, Brunner HG, de Brouwer AP, Kremer H. Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss. Hum Mutat. 2005 Dec;26(6):591. PubMed citation

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Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J, Makishima T, Ghosh M, Menon PS, Deshmukh D, Oddoux C, Ostrer H, Khan S, Riazuddin S, Deininger PL, Hampton LL, Sullivan SL, Battey JF Jr, Keats BJ, Wilcox ER, Friedman TB, Griffith AJ. Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet. 2002 Mar;30(3):277-84. Epub 2002 Feb 19. PubMed citation

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Kurima K, Yang Y, Sorber K, Griffith AJ. Characterization of the transmembrane channel-like (TMC) gene family: functional clues from hearing loss and epidermodysplasia verruciformis small star, filled. Genomics. 2003 Sep;82(3):300-8. PubMed citation

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Makishima T, Kurima K, Brewer CC, Griffith AJ. Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss. Otol Neurotol. 2004 Sep;25(5):714-9. PubMed citation

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What Is the Official Name of the TMIE Gene?30 The official name of this gene is “transmembrane inner ear.” TMIE is the gene's official symbol. The TMIE gene is also known by other names, listed below.

What Is the Normal Function of the TMIE Gene? The TMIE gene provides instructions for making a protein called the transmembrane inner ear protein. Although the function of this protein is unknown, it appears to be important for normal hearing. Some studies have indicated that the protein may play a role in the development of hairlike projections called stereocilia in the inner ear. Stereocilia bend in response to sound waves, and this bending motion triggers a series of reactions that convert sound to nerve impulses. The transmembrane inner ear protein also may be necessary for the normal function of the auditory nerve, which transmits nerve impulses from the inner ear to the brain to allow the perception of sound.

What Conditions Are Related to the TMIE Gene? Nonsyndromic Deafness - Caused by Mutations in the TMIE Gene At least five mutations in the TMIE gene have been identified in families with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB6. Several of these genetic changes alter a single DNA building block (nucleotide) in the TMIE gene. Other mutations insert or delete a small 30

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=tmie;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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amount of DNA in the gene. Researchers have not determined how these mutations lead to hearing loss.

Where Is the TMIE Gene Located? Cytogenetic Location: 3p21

Molecular Location on chromosome 3: base pairs 46,717,826 to 46,727,204 The TMIE gene is located on the short (p) arm of chromosome 3 at position 21.

References These sources were used to develop the Genetics Home Reference gene summary on the TMIE gene. •

Mitchem KL, Hibbard E, Beyer LA, Bosom K, Dootz GA, Dolan DF, Johnson KR, Raphael Y, Kohrman DC. Mutation of the novel gene Tmie results in sensory cell defects in the inner ear of spinner, a mouse model of human hearing loss DFNB6. Hum Mol Genet. 2002 Aug 1;11(16):1887-98. PubMed citation

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Naz S, Giguere CM, Kohrman DC, Mitchem KL, Riazuddin S, Morell RJ, Ramesh A, Srisailpathy S, Deshmukh D, Riazuddin S, Griffith AJ, Friedman TB, Smith RJ, Wilcox ER. Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am J Hum Genet. 2002 Sep;71(3):632-6. Epub 2002 Jul 24. PubMed citation

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Santos RL, El-Shanti H, Sikandar S, Lee K, Bhatti A, Yan K, Chahrour MH, McArthur N, Pham TL, Mahasneh AA, Ahmad W, Leal SM. Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment. J Mol Med. 2006 Mar;84(3):226-31. Epub 2005 Dec 31. PubMed citation

What Is the Official Name of the TMPRSS3 Gene?31 The official name of this gene is “transmembrane protease, serine 3.” 31

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=tmprss3.

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TMPRSS3 is the gene's official symbol. The TMPRSS3 gene is also known by other names, listed below.

What Is the Normal Function of the TMPRSS3 Gene? The TMPRSS3 gene provides instructions for making a protein that is part of a large protein family called serine proteases. Serine proteases are enzymes that are involved in many normal biological functions, including digestion, blood clotting, and inflammation. These enzymes have an active center that cuts apart (cleaves) other proteins into smaller pieces. They are called serine proteases because the active center contains a molecule called serine. Serine is a type of amino acid, which is a building block found in many proteins. The exact function of the protein made by the TMPRSS3 gene is unknown, but it appears to be essential for normal hearing. The protein likely plays a role in the development and maintenance of the inner ear, and is also present in many other tissues. Researchers believe that the TMPRSS3 protein activates a protein called the epithelial amiloride sensitive sodium channel (ENaC), which probably controls important chemical signaling pathways in the inner ear.

What Conditions Are Related to the TMPRSS3 Gene? Nonsyndromic Deafness - Caused by Mutations in the TMPRSS3 Gene More than 10 mutations in the TMPRSS3 gene have been reported in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB8/10. Studies suggest that mutations in this gene may be a significant cause of nonsyndromic deafness in the Turkish population. Cancers - Associated with the TMPRSS3 Gene More than 10 mutations in the TMPRSS3 gene have been reported in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB8/10. Studies suggest that mutations in this gene may be a significant cause of nonsyndromic deafness in the Turkish population.

Where Is the TMPRSS3 Gene Located? Cytogenetic Location: 21q22.3

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Molecular Location on chromosome 21: base pairs 42,665,067 to 42,689,268 The TMPRSS3 gene is located on the long (q) arm of chromosome 21 at position 22.3.

References These sources were used to develop the Genetics Home Reference gene summary on the TMPRSS3 gene. •

Ahmed ZM, Li XC, Powell SD, Riazuddin S, Young TL, Ramzan K, Ahmad Z, Luscombe S, Dhillon K, MacLaren L, Ploplis B, Shotland LI, Ives E, Riazuddin S, Friedman TB, Morell RJ, Wilcox ER. Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan. BMC Med Genet. 2004 Sep 24;5:24. PubMed citation

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Ben-Yosef T, Wattenhofer M, Riazuddin S, Ahmed ZM, Scott HS, Kudoh J, Shibuya K, Antonarakis SE, Bonne-Tamir B, Radhakrishna U, Naz S, Ahmed Z, Riazuddin S, Pandya A, Nance WE, Wilcox ER, Friedman TB, Morell RJ. Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. J Med Genet. 2001 Jun;38(6):396-400. No abstract available. PubMed citation

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Guipponi M, Vuagniaux G, Wattenhofer M, Shibuya K, Vazquez M, Dougherty L, Scamuffa N, Guida E, Okui M, Rossier C, Hancock M, Buchet K, Reymond A, Hummler E, Marzella PL, Kudoh J, Shimizu N, Scott HS, Antonarakis SE, Rossier BC. The transmembrane serine protease (TMPRSS3) mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro. Hum Mol Genet. 2002 Nov 1;11(23):282936. PubMed citation

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Lee YJ, Park D, Kim SY, Park WJ. Pathogenic mutations but not polymorphisms in congenital and childhood onset autosomal recessive deafness disrupt the proteolytic activity of TMPRSS3. J Med Genet. 2003 Aug;40(8):629-31. No abstract available. PubMed citation

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Sawasaki T, Shigemasa K, Gu L, Beard JB, O'Brien TJ. The transmembrane protease serine (TMPRSS3/TADG-12) D variant: a potential candidate for diagnosis and therapeutic intervention in ovarian cancer. Tumour Biol. 2004 May-Jun;25(3):141-8. PubMed citation

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Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J, Kawasaki K, Asakawa S, Minoshima S, Younus F, Mehdi SQ, Radhakrishna U, Papasavvas MP, Gehrig C, Rossier C, Korostishevsky M, Gal A, Shimizu N, Bonne-

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Tamir B, Antonarakis SE. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet. 2001 Jan;27(1):59-63. PubMed citation •

Underwood LJ, Shigemasa K, Tanimoto H, Beard JB, Schneider EN, Wang Y, Parmley TH, O'Brien TJ. Ovarian tumor cells express a novel multi-domain cell surface serine protease. Biochim Biophys Acta. 2000 Nov 15;1502(3):337-50. PubMed citation

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Wallrapp C, Hahnel S, Muller-Pillasch F, Burghardt B, Iwamura T, Ruthenburger M, Lerch MM, Adler G, Gress TM. A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Cancer Res. 2000 May 15;60(10):2602-6. PubMed citation

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Wattenhofer M, Sahin-Calapoglu N, Andreasen D, Kalay E, Caylan R, Braillard B, Fowler-Jaeger N, Reymond A, Rossier BC, Karaguzel A, Antonarakis SE. A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein. Hum Genet. 2005 Jul 14; [Epub ahead of print]. PubMed citation

What Is the Official Name of the TRIOBP Gene?32 The official name of this gene is “TRIO and F-actin binding protein.” TRIOBP is the gene's official symbol. The TRIOBP gene is also known by other names, listed below.

What Is the Normal Function of the TRIOBP Gene? The TRIOBP gene provides instructions for making a protein called TRIO and F-actin binding protein (Triobp). Within cells, the Triobp protein likely regulates aspects of the cytoskeleton, the structural framework that helps to determine cell shape, size, and movement. The Triobp protein is thought to help control the organization of actin filaments, which are long, thin fibers that make up a significant part of the cytoskeleton. Actin filaments are necessary for several normal cellular functions, such as cell division, cell movement (motility), maintenance of cell shape, transport of proteins and other molecules within cells, and chemical signaling between cells. There are two versions of Triobp, a short version found in most body tissues, and a long version made only in the brain, the eye, and the inner ear. Because of its presence in the inner ear, especially the snail-shaped structure called the cochlea, researchers are interested in this protein's role in hearing. Triobp probably plays a role in the development and maintenance of stereocilia, which are hairlike projections that line the inner ear. Stereocilia, which are rich in actin, bend in response to sound waves. This bending motion is essential for converting sound waves to nerve impulses, a critical process for normal hearing.

32

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=triobp;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Conditions Are Related to the TRIOBP Gene? Nonsyndromic Deafness - Caused by Mutations in the TRIOBP Gene Researchers have identified at least nine TRIOBP mutations that cause a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB28. Almost all of these mutations introduce a premature stop signal in the instructions for making the long version of Triobp. As a result, an abnormally small version of this protein is made in the brain and inner ear. The abnormal protein probably cannot interact with the actin filaments within stereocilia, leading to hearing loss.

Where Is the TRIOBP Gene Located? Cytogenetic Location: 22q13.1

Molecular Location on chromosome 22: base pairs 36,423,573 to 36,502,508 The TRIOBP gene is located on the long (q) arm of chromosome 22 at position 13.1.

References These sources were used to develop the Genetics Home Reference gene summary on the TRIOBP gene. •

Entrez Gene

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Riazuddin S, Khan SN, Ahmed ZM, Ghosh M, Caution K, Nazli S, Kabra M, Zafar AU, Chen K, Naz S, Antonellis A, Pavan WJ, Green ED, Wilcox ER, Friedman PL, Morell RJ, Riazuddin S, Friedman TB. Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness. Am J Hum Genet. 2006 Jan;78(1):137-43. Epub 2005 Nov 21. PubMed citation

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Seipel K, O'Brien SP, Iannotti E, Medley QG, Streuli M. Tara, a novel F-actin binding protein, associates with the Trio guanine nucleotide exchange factor and regulates actin cytoskeletal organization. J Cell Sci. 2001 Jan;114(Pt 2):389-99. PubMed citation

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Shahin H, Walsh T, Sobe T, Abu Sa'ed J, Abu Rayan A, Lynch ED, Lee MK, Avraham KB, King MC, Kanaan M. Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. Am J Hum Genet. 2006 Jan;78(1):144-52. Epub 2005 Nov 21. PubMed citation

What Is the Official Name of the USH1C Gene?33 The official name of this gene is “Usher syndrome 1C (autosomal recessive, severe).” USH1C is the gene's official symbol. The USH1C gene is also known by other names, listed below.

What Is the Normal Function of the USH1C Gene? The USH1C gene carries the instructions for the production of a protein called harmonin. Harmonin has the ability to bind to many other proteins in cell membranes and coordinates their activities. Harmonin sometimes acts as a bridge linking proteins in the cell membrane to those in the cytoskeleton, the internal framework that supports the cell. Research suggests that harmonin plays a role in the development and maintenance of hairlike projections called stereocilia. Stereocilia line the inner ear and bend in response to sound waves. This bending motion is critical for converting sound waves to nerve impulses, an essential process for normal hearing. In the inner ear, protein complexes organized by harmonin probably act as connectors that link stereocilia into a bundle. This protein complex likely helps regulate the transmission of sound waves. Harmonin is also made in specialized cells called photoreceptors. These cells detect and transfer light energy to the light-sensitive tissue at the back of the eye (the retina). The function of the harmonin-protein complex in the retina is not well understood, but it is thought to be important in the development and function of photoreceptor cells.

What Conditions Are Related to the USH1C Gene? Nonsyndromic Deafness - Caused by Mutations in the USH1C Gene At least one mutation in the USH1C gene causes a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB18. This mutation changes a single DNA building block (base pair), which disrupts the instructions for producing harmonin. The abnormal version of harmonin causes defects in the stereocilia, leading to hearing loss. Usher Syndrome - Caused by Mutations in the USH1C Gene At least one mutation in the USH1C gene causes a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB18. This mutation changes a single DNA building block (base pair), which disrupts the 33

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=ush1c.

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instructions for producing harmonin. The abnormal version of harmonin causes defects in the stereocilia, leading to hearing loss.

Where Is the USH1C Gene Located? Cytogenetic Location: 11p14.3

Molecular Location on chromosome 11: base pairs 17,472,017 to 17,522,538 The USH1C gene is located on the short (p) arm of chromosome 11 at position 14.3.

References These sources were used to develop the Genetics Home Reference gene summary on the USH1C gene. •

Adato A, Michel V, Kikkawa Y, Reiners J, Alagramam KN, Weil D, Yonekawa H, Wolfrum U, El-Amraoui A, Petit C. Interactions in the network of Usher syndrome type 1 proteins. Hum Mol Genet. 2005 Feb 1;14(3):347-56. Epub 2004 Dec 8. PubMed citation

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Ahmed ZM, Smith TN, Riazuddin S, Makishima T, Ghosh M, Bokhari S, Menon PS, Deshmukh D, Griffith AJ, Riazuddin S, Friedman TB, Wilcox ER. Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC. Hum Genet. 2002 Jun;110(6):527-31. Epub 2002 May 03. PubMed citation

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Blaydon DC, Mueller RF, Hutchin TP, Leroy BP, Bhattacharya SS, Bird AC, Malcolm S, Bitner-Glindzicz M. The contribution of USH1C mutations to syndromic and nonsyndromic deafness in the UK. Clin Genet. 2003 Apr;63(4):303-7. PubMed citation

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OMIM: USH1C gene

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Ouyang XM, Xia XJ, Verpy E, Du LL, Pandya A, Petit C, Balkany T, Nance WE, Liu XZ. Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. Hum Genet. 2002 Jul;111(1):26-30. Epub 2002 Jun 18. PubMed citation

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Petit C. Usher syndrome: from genetics to pathogenesis. Annu Rev Genomics Hum Genet. 2001;2:271-97. Review. PubMed citation

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Reiners J, van Wijk E, Marker T, Zimmermann U, Jurgens K, te Brinke H, Overlack N, Roepman R, Knipper M, Kremer H, Wolfrum U. Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Hum Mol Genet. 2005 Dec 15;14(24):3933-43. Epub 2005 Nov 21. PubMed citation

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Savas S, Frischhertz B, Pelias MZ, Batzer MA, Deininger PL, Keats BB. The USH1C 216G-->A mutation and the 9-repeat VNTR(t,t) allele are in complete linkage disequilibrium in the Acadian population. Hum Genet. 2002 Jan;110(1):95-7. Epub 2001 Dec 06. PubMed citation

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Siemens J, Kazmierczak P, Reynolds A, Sticker M, Littlewood-Evans A, Muller U. The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZdomain interactions. Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14946-51. Epub 2002 Oct 29. PubMed citation

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Verpy E, Leibovici M, Zwaenepoel I, Liu XZ, Gal A, Salem N, Mansour A, Blanchard S, Kobayashi I, Keats BJ, Slim R, Petit C. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet. 2000 Sep;26(1):51-5. PubMed citation

What Is the Official Name of the WFS1 Gene?34 The official name of this gene is “Wolfram syndrome 1 (wolframin).” WFS1 is the gene's official symbol. The WFS1 gene is also known by other names, listed below.

34

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=wfs1;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Is the Normal Function of the WFS1 Gene? The WFS1 gene provides instructions for making a protein called wolframin. The WFS1 gene is active in cells throughout the body, with strong activity in the heart, brain, lungs, inner ear, and pancreas. The pancreas provides enzymes that help digest food, and it also produces the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy. Within cells, wolframin is located in a structure called the endoplasmic reticulum. Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape to function properly. The endoplasmic reticulum also helps transport proteins, fats, and other materials to specific sites within the cell or to the cell surface. The function of wolframin is unknown. Based on its location in the endoplasmic reticulum, however, it may play a role in protein folding or cellular transport. In the pancreas, wolframin may help fold a protein precursor of insulin (called proinsulin) into the mature hormone that controls blood glucose levels. Research findings also suggest that wolframin may help maintain the correct cellular level of charged calcium atoms (calcium ions) by controlling how much is stored in the endoplasmic reticulum. In the inner ear, wolframin may help maintain the proper levels of calcium ions or other charged particles that are essential for hearing.

What Conditions Are Related to the WFS1 Gene? Nonsyndromic Deafness - Caused by Mutations in the WFS1 Gene More than 30 WFS1 mutations have been identified in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA6. Individuals with DFNA6 deafness cannot hear low tones (low-frequency sounds), such as a tuba or the "m" in moon. DFNA6 hearing loss is unlike most forms of nonsyndromic deafness that affect high tones (high-frequency sounds), such as birds chirping, or all frequencies of sound. Most WFS1 mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. One mutation deletes an amino acid from wolframin. WFS1 mutations probably alter the 3dimensional shape of wolframin, which could affect its function. Because the function of wolframin is unknown, however, it is unclear how WFS1 mutations cause hearing loss. Some researchers suggest that altered wolframin disturbs the balance of charged particles in the inner ear, which interferes with the hearing process. Other Disorders - Caused by Mutations in the WFS1 Gene More than 30 WFS1 mutations have been identified in individuals with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA6. Individuals with DFNA6 deafness cannot hear low tones (low-frequency sounds), such as a tuba or the "m" in moon. DFNA6 hearing loss is unlike most forms of nonsyndromic deafness that affect high tones (high-frequency sounds), such as birds chirping, or all frequencies of sound. Most WFS1 mutations replace one of the protein building blocks (amino acids) used to make wolframin with an incorrect amino acid. One mutation deletes an amino acid from wolframin. WFS1 mutations probably alter the 3dimensional shape of wolframin, which could affect its function. Because the function of

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wolframin is unknown, however, it is unclear how WFS1 mutations cause hearing loss. Some researchers suggest that altered wolframin disturbs the balance of charged particles in the inner ear, which interferes with the hearing process.

Where Is the WFS1 Gene Located? Cytogenetic Location: 4p16

Molecular Location on chromosome 4: base pairs 6,322,477 to 6,355,892 The WFS1 gene is located on the short (p) arm of chromosome 4 at position 16.

References These sources were used to develop the Genetics Home Reference gene summary on the WFS1 gene. •

Bespalova IN, Van Camp G, Bom SJ, Brown DJ, Cryns K, DeWan AT, Erson AE, Flothmann K, Kunst HP, Kurnool P, Sivakumaran TA, Cremers CW, Leal SM, Burmeister M, Lesperance MM. Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum Mol Genet. 2001 Oct 15;10(22):2501-8. PubMed citation

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Cryns K, Pfister M, Pennings RJ, Bom SJ, Flothmann K, Caethoven G, Kremer H, Schatteman I, Koln KA, Toth T, Kupka S, Blin N, Nurnberg P, Thiele H, van de Heyning PH, Reardon W, Stephens D, Cremers CW, Smith RJ, Van Camp G. Mutations in the WFS1 gene that cause low-frequency sensorineural hearing loss are small noninactivating mutations. Hum Genet. 2002 May;110(5):389-94. Epub 2002 Apr 09. PubMed citation

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Cryns K, Sivakumaran TA, Van Den Ouweland JM, Pennings RJ, Cremers CW, Flothmann K, Young TL, Smith RJ, Lesperance MM, Camp GV. Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Hum Mutat. 2003 Oct;22(4):275-87. PubMed citation

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Cryns K, Thys S, Van Laer L, Oka Y, Pfister M, Van Nassauw L, Smith RJ, Timmermans JP, Van Camp G. The WFS1 gene, responsible for low frequency sensorineural hearing loss and Wolfram syndrome, is expressed in a variety of inner ear cells. Histochem Cell Biol. 2003 Mar;119(3):247-56. Epub 2003 Feb 19. PubMed citation

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Gurtler N, Kim Y, Mhatre A, Schlegel C, Mathis A, Daniels R, Shelton C, Lalwani AK. Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1. J Mol Med. 2005 Jul;83(7):553-60. Epub 2005 May 24. PubMed citation

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Hofmann S, Bauer MF. Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin. FEBS Lett. 2006 Jul 10;580(16):4000-4. Epub 2006 Jun 22. PubMed citation

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Hofmann S, Philbrook C, Gerbitz KD, Bauer MF. Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product. Hum Mol Genet. 2003 Aug 15;12(16):2003-12. PubMed citation

What Is the Official Name of the MT-RNR1 Gene?35 The official name of this gene is “mitochondrially encoded 12S RNA.” MT-RNR1 is the gene's official symbol. The MT-RNR1 gene is also known by other names, listed below.

What Is the Normal Function of the MT-RNR1 Gene? The MT-RNR1 gene provides instructions for making a particular type of RNA, a molecule that is a chemical cousin of DNA. This type of RNA, known as ribosomal RNA (rRNA), is involved in the assembly of proteins within cells. The MT-RNR1 gene provides instructions for a specific form of ribosomal RNA called 12S RNA, which is present only in cellular structures called mitochondria. These structures convert energy from food into a form that cells can use. Through a process called oxidative phosphorylation, mitochondria use oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source. 12S RNA molecules help assemble protein building blocks (amino acids) into the functioning proteins that carry out oxidative phosphorylation.

What Conditions Are Related to the MT-RNR1 Gene? Nonsyndromic Deafness - Increased Risk from Variations of the MT-RNR1 Gene Several mutations in the MT-RNR1 gene can increase the risk of developing nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body). If people with MT-RNR1 mutations are exposed to antibiotic medications known as aminoglycosides, they almost always develop permanent hearing loss within days to weeks 35

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=mtrnr1.

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of taking the medication. This group of antibiotics is typically used to treat chronic bacterial infections such as tuberculosis. Deafness resulting from exposure to these antibiotics is known as aminoglycoside ototoxicity.

Where Is the MT-RNR1 Gene Located? The MT-RNR1 gene is located in

Molecular Location in mitochondrial DNA: base pairs 649 to 1,602 You and your healthcare professional may find the following resources about MT-RNR1 helpful.

References These sources were used to develop the Genetics Home Reference gene summary on the MT-RNR1 gene. •


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Fischel-Ghodsian N. Genetic factors in aminoglycoside toxicity. Pharmacogenomics. 2005 Jan;6(1):27-36. PubMed citation

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Gene Review: Nonsyndromic Hearing Loss and Deafness, Mitochondrial

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Giordano C, Pallotti F, Walker WF, Checcarelli N, Musumeci O, Santorelli F, d'Amati G, Schon EA, DiMauro S, Hirano M, Davidson MM. Pathogenesis of the deafnessassociated A1555G mitochondrial DNA mutation. Biochem Biophys Res Commun. 2002 Apr 26;293(1):521-9. PubMed citation

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Zhao H, Young WY, Yan Q, Li R, Cao J, Wang Q, Li X, Peters JL, Han D, Guan MX. Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss. Nucleic Acids Res. 2005 Feb 18;33(3):1132-9. Print 2005. PubMed citation

What Is the Official Name of the ATP2B2 Gene?36 The official name of this gene is “ATPase, Ca++ transporting, plasma membrane 2.” ATP2B2 is the gene's official symbol. The ATP2B2 gene is also known by other names, listed below.

What Is the Normal Function of the ATP2B2 Gene? The ATP2B2 gene provides instructions for making an enzyme called plasma membrane calcium-transporting ATPase 2 (PMCA2). This enzyme belongs to a family of ATPase enzymes that helps control the level of positively charged calcium atoms (calcium ions) inside cells. Calcium ions act as signals for a large number of activities that are important for the normal development and function of cells. PMCA2 appears to be important for regulating calcium ion levels in certain cells in the brain, spinal cord, liver, inner ear, and in the breast when milk is produced. Researchers are interested in PMCA2's role in hearing because of its presence in the inner ear. Hearing requires the conversion of sound waves to nerve impulses that are transmitted via the auditory nerve to the brain. This conversion process occurs in specialized cells called hair cells and is triggered by a rapid change in the level of certain ions, including calcium ions. Studies indicate that PMCA2 exports calcium ions from hair cells and contributes to changes in ion levels that are needed for the conversion of sound waves to nerve impulses.

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=atp2b2;jsessionid=69A929A63846F53F5C2A13395CDE0486.

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What Conditions Are Related to the ATP2B2 Gene? Nonsyndromic Deafness - Course of Condition Modified by Variations in the ATP2B2 Gene Researchers have identified one variation in the ATP2B2 gene that appears to affect the severity of hearing loss. This variation changes one of the building blocks (amino acids) used to make the PMCA2 enzyme. Specifically, the amino acid valine is replaced with the amino acid methionine at position 586 in the enzyme (written as Val586Met). In a small number of people, researchers found that this particular variation occurs with mutations in another gene (called CDH23) that causes hearing loss. In these individuals, hearing loss is more severe than in people who have mutations in the CDH23 gene but lack the ATP2B2 variation. The Val586Met variation in the ATP2B2 gene might also modify hearing loss when it occurs with a mutation in another hearing loss gene called MYO6. Mutations in the CDH23 and MYO6 genes impair the conversion of sound waves to nerve impulses. It remains unclear how the variation in the ATP2B2 gene further impairs hearing loss.

Where Is the ATP2B2 Gene Located? Cytogenetic Location: 3p25.3

Molecular Location on chromosome 3: base pairs 10,342,743 to 10,466,545 The ATP2B2 gene is located on the short (p) arm of chromosome 3 at position 25.3.

References These sources were used to develop the Genetics Home Reference gene summary on the ATP2B2 gene. •

Guerini D, Coletto L, Carafoli E. Exporting calcium from cells. Cell Calcium. 2005 SepOct;38(3-4):281-9. Review. PubMed citation

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Schultz JM, Yang Y, Caride AJ, Filoteo AG, Penheiter AR, Lagziel A, Morell RJ, Mohiddin SA, Fananapazir L, Madeo AC, Penniston JT, Griffith AJ. Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med. 2005

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Apr 14;352(15):1557-64. Erratum in: N Engl J Med. 2005 Jun 2;352(22):2362. PubMed citation

What Is the Official Name of the GJB3 Gene?37 The official name of this gene is “gap junction protein, beta 3, 31kDa (connexin 31).” GJB3 is the gene's official symbol. The GJB3 gene is also known by other names, listed below.

What Is the Normal Function of the GJB3 Gene? The GJB3 gene provides instructions for making a protein called gap junction beta 3, more commonly known as connexin 31. Connexin 31 is a member of the connexin protein family. Connexin proteins form channels called gap junctions that permit the transport of nutrients, charged atoms (ions), and signaling molecules between neighboring cells. Connexin 31 is found in several different tissues throughout the body, including the skin, the inner ear, and the nerve that connects the inner ear with the brain (the auditory nerve). Connexin 31 plays a role in the growth and maturation of the outermost layer of skin (the epidermis). The presence of this protein in the inner ear and auditory nerve suggests that it may be involved in hearing. Hearing requires the conversion of sound waves to electrical nerve impulses, which travel along the auditory nerve to the brain. The exact role of connexin 31 in the inner ear and auditory nerve is unclear.

What Conditions Are Related to the GJB3 Gene? Nonsyndromic Deafness - Associated with the GJB3 Gene Researchers have identified a few GJB3 mutations in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA2. DFNA2 deafness is inherited in an autosomal dominant manner, which means that one copy of the GJB3 gene in each cell is altered. A few GJB3 mutations have also been identified in people with autosomal recessive nonsyndromic deafness. This type of inheritance means that two copies of the GJB3 gene in each cell are altered. It is unclear, however, whether GJB3 mutations are the direct cause of hearing loss in individuals with either of these types of deafness. Other Disorders - Caused by Mutations in the GJB3 Gene Researchers have identified a few GJB3 mutations in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA2. DFNA2 deafness is inherited in an autosomal dominant manner, which means that one copy of the GJB3 gene in each cell is altered. A few GJB3 mutations have also 37

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=gjb3.

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been identified in people with autosomal recessive nonsyndromic deafness. This type of inheritance means that two copies of the GJB3 gene in each cell are altered. It is unclear, however, whether GJB3 mutations are the direct cause of hearing loss in individuals with either of these types of deafness.

Where Is the GJB3 Gene Located? Cytogenetic Location: 1p34

Molecular Location on chromosome 1: base pairs 35,019,376 to 35,024,553 The GJB3 gene is located on the short (p) arm of chromosome 1 at position 34.


Alexandrino F, Oliveira CA, Reis FC, Maciel-Guerra AT, Sartorato EL. Screening for mutations in the GJB3 gene in Brazilian patients with nonsyndromic deafness. J Appl Genet. 2004;45(2):249-54. PubMed citation

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Diestel S, Richard G, Doring B, Traub O. Expression of a connexin31 mutation causing erythrokeratodermia variabilis is lethal for HeLa cells. Biochem Biophys Res Commun. 2002 Aug 23;296(3):721-8. PubMed citation

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Frei K, Ramsebner R, Hamader G, Lucas T, Schoefer C, Baumgartner WD, Wachtler FJ, Kirschhofer K. Lack of association between Connexin 31 (GJB3) alterations and sensorineural deafness in Austria. Hear Res. 2004 Aug;194(1-2):81-6. PubMed citation

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Rabionet R, Lopez-Bigas N, Arbones ML, Estivill X. Connexin mutations in hearing loss, dermatological and neurological disorders. Trends Mol Med. 2002 May;8(5):205-12. Review. PubMed citation

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Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH Jr, DiGiovanna JJ, Compton JG, Bale SJ. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis. Nat Genet. 1998 Dec;20(4):366-9. PubMed citation

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What Is the Official Name of the MYO1A Gene?38 The official name of this gene is “myosin IA.” MYO1A is the gene's official symbol. The MYO1A gene is also known by other names, listed below.

What Is the Normal Function of the MYO1A Gene? The MYO1A gene provides instructions for making a protein called myosin IA, which is part of a group of proteins called unconventional myosins. These proteins, which have similar structures, each play a role in transporting molecules within cells. Myosins interact with actin, a protein that is important for cell movement and shape. Researchers believe that myosins use long filaments of actin as tracks along which to transport other molecules. Myosin IA is made in intestinal epithelial cells, which are cells that line the walls of the intestine. These cells have fingerlike projections called microvilli that absorb nutrients from food as it passes through the intestine. Based on their appearance, groups of these microvilli are known collectively as the brush border. Microvilli contain bundles of actin filaments that provide structural support and are used for internal transport. Although the precise function of the myosin IA protein is unknown, it is active in the brush border and is probably involved in transporting nutrients from food. Myosin IA is also present in the inner ear and appears to be involved in normal hearing. Researchers have not determined the protein's role in the inner ear.

What Conditions Are Related to the MYO1A Gene? Nonsyndromic Deafness - Associated with the MYO1A Gene At least eight mutations in the MYO1A gene have been identified in people with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNA48. Most of these genetic changes alter single protein building blocks (amino acids) in the myosin IA protein. In one case, a mutation adds an extra amino acid to the protein. These mutations probably alter the structure of myosin IA or cause an abnormally small, nonfunctional version of the protein to be made. Researchers have not determined how mutations in the MYO1A gene could result in hearing loss, and it remains unclear whether MYO1A mutations impair hearing. 38


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Where Is the MYO1A Gene Located? Cytogenetic Location: 12q13-q15

Molecular Location on chromosome 12: base pairs 55,708,567 to 55,730,159 The MYO1A gene is located on the long (q) arm of chromosome 12 between positions 13 and 15.


Donaudy F, Ferrara A, Esposito L, Hertzano R, Ben-David O, Bell RE, Melchionda S, Zelante L, Avraham KB, Gasparini P. Multiple mutations of MYO1A, a cochlearexpressed gene, in sensorineural hearing loss. Am J Hum Genet. 2003 Jun;72(6):1571-7. Epub 2003 May 06. PubMed citation

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Tyska MJ, Mackey AT, Huang JD, Copeland NG, Jenkins NA, Mooseker MS. Myosin-1a is critical for normal brush border structure and composition. Mol Biol Cell. 2005 May;16(5):2443-57. Epub 2005 Mar 9. PubMed citation

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Tyska MJ, Mooseker MS. A role for myosin-1A in the localization of a brush border disaccharidase. J Cell Biol. 2004 May 10;165(3):395-405. PubMed citation

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Tyska MJ, Mooseker MS. MYO1A (brush border myosin I) dynamics in the brush border of LLC-PK1-CL4 cells. Biophys J. 2002 Apr;82(4):1869-83. PubMed citation

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Federally Funded Research on Nonsyndromic Deafness The U.S. Government supports a variety of research studies relating to nonsyndromic deafness. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.39 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP 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 nonsyndromic deafness. 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 nonsyndromic deafness. The following is typical of the type of information found when searching the CRISP database for nonsyndromic deafness: •

Project Title: CONNEXIN MUTATIONS IN DEAFNESS Principal Investigator & Institution: White, Thomas W.; Assistant Professor; Physiology and Biophysics; State University New York Stony Brook Stony Brook, Ny 11794 Timing: Fiscal Year 2005; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Mutations in the human connexin26 gene (Cx26, or GJB2) are the leading cause of nonsyndromic deafness in the United States. Mutations in other connexins, Cx30 (GJB6), Cx31 (GJB3), and Cx32 (GJB1) have also been linked to hearing loss in humans. While this illuminates a critical function for cochlear gap junctions, it is unclear how a common pathology can arise from mutations within different connexin genes that have an overlapping expression pattern in the inner ear, as is the case for Cx26, Cx30, Cx31 and Cx32. There are no gap junctions between the sensory hair cells in humans; but they are expressed in the supporting cells of the cochlea. The current hypothesis is that these junctions play a role in the re-circulation of potassium ions between the end lymph and perilymph. It is difficult to reconcile this model with the available data on potassium permeation through gap junction channels, as all connexins are readily permeated by this caution and the loss of a single cochlear connexin would still leave other functional connexins available to perform this task. Connexins do show differential permeability to a wide range of other small molecules and second messengers, and we hypothesize that these permeation differences are critical for cochlear function, and more difficult to compensate for following the functional loss of one of the several available channel subunits. The objective of this application is to precisely define which permeation properties of Cx26 are necessary for normal auditory function in humans. To achieve this goal, we first propose to screen mutant Cx26 alleles for functional activity in the paired Xenopus oocyte assay. Cx26 mutants that retain channel function will have their perm selectivity properties analyzed by dual patch clamp methods in transected mammalian cell lines. Finally, We will generate and characterize genetically engineered mice where the native Cx26 gene has

39 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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been replaced by the functionally active human Cx26 disease causing mutations. We will use genetic knock-in techniques to generate mice that will allow us to evaluate the in vitro derived functional differences in an animal model. Contrasting the differences in permeation between wild type and disease causing variants of Cx26 will not only provide mechanistic insight into hearing loss, but will also provide a general model for the need for connexin diversity in other tissues where human disease results from mutations in connexin genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IDENTIFICATION AND FUNCTIONAL ANALYSIS OF THE MOUSE DEAF Principal Investigator & Institution: Kohrman, David C.; Associate Professor; Otolaryngology; University of Michigan at Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2005; Project Start 01-APR-2001; Project End 31-MAR-2007 Summary: (Adapted from applicant's abstract): The primary objective of this proposal is the identification and characterization of the gene responsible for inherited deafness in the mouse mutant known as 'spinner'. Mutation of this gene results in sensorineural hearing loss similar to that found in many human nonsyndromic deafness disorders. The approaches described will attempt to correlate effects at the single gene level with those occurring at the cellular level and the level of the intact cochlea. A positional cloning strategy will be used to identify the affected gene. Gene localization information will be derived from an existing high resolution genetic cross and a set of genomic DNA clones that span the candidate region. Positional candidate genes mapped to this region in mouse, and to the region of conserved linkage in humans, will be evaluated for mutation in spinner mice. To further narrow the candidate region, genomic DNA clones from the candidate region will be microinjected into sr/sr zygotes. DNA clones that contain a functional version of the normal gene are expected to produce phenotypic correction in the resulting transgenic progeny. This DNA will be directly screened for the presence of the affected gene. The biological role of the spinner gene in the cochlea will be examined using several approaches. High resolution phenotypic analysis of affected mice will be performed to identify early defects in the cochlea that result from mutation of the spinner gene. Sensory cell function in the cochlea will be assessed by measurement of evoked responses in spinner mice. Ultrastructural and immunocytochemical analyses will be performed to detail the degenerative process in the mutant cochlea. Database analysis of the gene's primary sequence will be used to identify related genes and protein motifs that may provide insight into gene function. The expression pattern of the spinner gene, and the subcellular localization of its encoded protein, will be determined. Based upon comparative genetic data, the human version of the spinner gene is a positional candidate for the gene affected in a nonsyndromic deafness disorder, DFNB6. The human gene will be directly evaluated for mutations in individuals with inherited defects at the DFNB6 locus. This project will result in the identification of a critical gene in the mammalian inner ear, provide the basis for a model of this gene's role in the cochlea, and investigate the involvement of the gene in human nonsyndromic hearing loss. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IDENTIFICATION OF NONSYNDROMIC HEARING IMPAIRMENT GENES Principal Investigator & Institution: Leal, Suzanne M.; Associate Professor; Molecular and Human Genetics; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 770303498 Timing: Fiscal Year 2005; Project Start 01-AUG-1998; Project End 31-JUL-2009 Summary: (provided by applicant): Hearing impairment has a major impact on affected individuals. It can profoundly influence communication, language acquisition, speech, cognitive skills and psychosocial development. More than 60 percent of the cases of profound early-onset deafness are caused by genetic factors, which in most cases are due to single gene mutations. Nonsyndromic hearing impairment (NSHI) is the most heterogeneous trait known. Thus far, over 90 genes have been localized for NSHL and 35 genes have been identified. The goals of this project are to continue to develop a resource of families with NSHL, map novel NSHL loci, refine the genetic regions for known NSHL loci and identify novel NSHL genes. Families have been ascertained from Switzerland, Jordan, Turkey, Pakistan and the United States. Currently, additional families are being ascertained in Pakistan, Jordan and the USA. For the families that have been ascertained, genome scans and fine mapping is carried to establish linkage and map the locus segregating in the family to the smallest possible genetic region. The genes responsible for low frequency NSHI (WFS1) and a form of high frequency NSHI (ACTG1) have been identified in two of the USA families. This study has also identified a number of novel loci (DFNA23, DFNA24, DFNB35, DFNB38, DFNB39, DFNB42, DFNB43, DFNB44 and DFNB45) for which the genes are currently unknown. In addition, for other families linkage has been established and the genetic region has been reduced (e.g. DFNB13, DFNB19) for known NSHI loci where the gene has not yet been identified. Gene identification is conducted in regions where a gene has not been identified to date by screening genes that map to the same physical region as the NSHI locus of interest. Sequencing will first be performed on those genes that are believed to be the strongest candidates. A gene will be considered a good candidate if it belongs to a class of genes that have previously been implicated in the hearing impairment phenotype, has a potential function in the role of hearing and/or is expressed within the cochlea based upon RT-PCR experiments and from information available in public databases. The importance of obtaining good clinical data is stressed in order to develop phenotype/genotype relationships. The study will also yield important information on the public health impact of certain genes/mutations within various populations. Technology has been developed at the Baylor Human Genome Sequencing Center to facilitate the sequencing of a large number of genes in a cost- and time-efficient manner and has been implemented in this study. Identification of novel genes for NSHI will aid in understanding the function of genes controlling the mechanism of hearing, which will in the future facilitate the development of intervention strategies to prevent and treat hearing impairment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR BASIS OF INHERITED DEAFNESS Principal Investigator & Institution: Corey, David P.; Professor of Neurobiology; Neurobiology; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2005; Project Start 01-JUL-1994; Project End 31-AUG-2008 Summary: (provided by applicant): The transcription factor Math1 is necessary for the development and survival of hair cells in the inner ear. At least some of the genes that

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are activated by Math1 in hair cells are therefore necessary for development of hair cells, and consequently are candidate genes for inherited deafness. Although over 70 gene loci for human nonsyndromic deafness have been found, the genes for only 14 have been identified. This study will help identify others. Moreover, adjacent supporting cells in cochlea can differentiate into hair cells if transfected with Math1, although other cell types cannot. Thus identification of the genes activated by Math1, and of the hair-cellspecific binding partners of Math1, may reveal genes that could promote regeneration of hair cells. Age-related hearing loss, which affects tens of millions of Americans, often results from the death of hair cells and could be ameliorated by the regeneration of hair cells from supporting cells. The proposed project seeks to identify genes activated by Math1 in hair cells, using GeneChips to screen RNAs derived from several different approaches. It will first identify class I basic helix-loop-helix transcription factors that form heteromultimers with Math1 in hair cells, using GeneChip data from normal hair cells, RT-PCR, and co-immunoprecipitation in transfected cells. It will then use GeneChips to identify candidate target genes of Math1, in a cochlea cell line transfected with Math1, in stablytransfected osteosarcoma cells with Math1 under a tetracycline repressor, and in mice lacking Math1. In a third aim, it will test these candidates by determining whether they are expressed in hair cells at an appropriate developmental phase, and whether Math1 can activate a reporter gene under the control of the candidate-gene promoter. Finally, the chromosomal locations of confirmed candidates will be compared to deafness loci in human and mouse, to produce additional candidates for deafness genes. Since Math1 is necessary and (in some cell types) sufficient for the generation of hair cells, this study should teach us much about how a hair cell becomes a hair cell. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGULATION OF MICROTUBULES BY RHO GTPASES Principal Investigator & Institution: Gundersen, Gregg G.; Associate Professor; Pathology; Columbia University Health Sciences Columbia University Medical Center New York, Ny 100323702 Timing: Fiscal Year 2005; Project Start 01-APR-2001; Project End 30-NOV-2005 Summary: (provided by applicant) Microtubules (MTs) are ubiquitous elements of the cytoskeleton that are essential for the generation of cellular asymmetry during development and differentiation. In undifferentiated cells, most MTs are highly dynamic, whereas in polarizing or differentiated cells, certain MTs become stabilized and organized into specific arrays that are necessary for supporting polarized cell function. In many cases, alterations in proteins that regulate the formation of these MT arrays result in disease. Thus, lissencephaly is caused by alterations in the Lisl protein, which affects dynein functions in cell division and polarity. The nonsyndromic deafness syndrome, DFNA1, is cause by mutations in human Dia, a protein we have found regulates microtubule stabilization in fibroblasts. Our overall goal in this project is to determine the molecular mechanisms controlling MT stabilization and polarization and to explore their significance for cell function using the simple model system of in vitro wound healing. We have found that there are two distinct molecular pathways that regulate MTs during cell polarization and migration into wounds. These pathways resemble those described in yeast, where they function to position the nucleus and spindle. This suggests that MT-based polarization pathways have been conserved from yeast to mammals. One pathway involves the stabilization of MT oriented toward the wound and is regulated by the small GTPase Rho and its downstream effector mDia. We will explore how mDia regulates MT stabilization during in vitro wound healing by

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identifying the domain(s) of mDia important for MT stabilization and by identifying downstream effectors of mDia. Human Dia is mutated in DFNA1, and we will test the possibility that the mutation in DFNA1 alters MT stabilization. The second -pathway involves the reorientation of the MT organizing center (MTOC) toward the leading edge of cells adjacent to the wound margin. We have found that MTOC reorientation is regulated by CDC42 and is controlled independently of MT stabilization. We will study dynein and other potential downstream effectors to understand how CDC42 regulates MTOC reorientation. Lisl protein interferes with dynein function when overexpressed and we will test whether Lis1 overexpression effects MTOC orientation. We will study whether inhibition of MT stabilization or MTOC reorientation interferes with the polarization of cells, the migration of the cells into the wound and other wound responses. These studies should establish the molecular pathways by which MTs are regulated in cells and will contribute to our understanding of how cell polarity is established by MTs in all eukaryotic cells. These studies will also contribute to our understand of the basic molecular pathways involved in wound responses and will help explore the basic cell biological consequences of mutations in human Dia that causes deafness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF CONNEXINS IN COCHLEAR FUNCTIONS Principal Investigator & Institution: Lin, Xi; Otolaryn & Head & Neck Surgery; Emory University 1784 North Decatur Road, Suite 510 Atlanta, Ga 30322 Timing: Fiscal Year 2006; Project Start 15-JAN-2006; Project End 31-DEC-2010 Summary: (provided by applicant): Connexins (Cxs) are membrane proteins constituting the gap junctions (GJs), which provide a regulated conduit for intercellular ionic (e.g., K+, Ca++) and biochemical (e.g., nutrients and signaling molecules) couplings. Genetic studies have linked more than 100 mutations in Cx genes to a large proportion of prelingual nonsyndromic deafness. Despite their importance in hearing, we know very little about the role Cxs play in the cochlea. Our long-term goal is to understand the molecular mechanisms maintaining homeostasis in the mammalian cochlea, especially the role played by the Cx family of proteins in the cochlea. In this 5year project, we plan to conduct three series of experiments utilizing a multidisciplinary approach to test the HYPOTHESIS that biochemical coupling mediated by heteromultimeric GJs assembled from Cx26 and Cx30 in the cochlea is required for normal hearing in mice. First, we will use an in vitro system to investigate whether some human Cx26 mutations linked to deafness specifically affect biochemical permeability of cochlear GJs. Since most cochlear GJs are constituted by heteromultimeric assembly of Cx26 and Cx30, therefore deleting one Cx gene does not necessarily eliminate GJ channels in the cochlea. Our second series of experiments will investigate whether GJ channels are still functional for ionic permeation in the cochlea of Cx30-/- mice. Using in situ preparations and biochemical assays, we will test whether a change in the molecular configuration of wild type GJs are responsible for deafness in Cx30-/- mice. In the last series of experiments we will rescue the hearing of Cx30-/- mice by transgenic expressions of either Cx30 or Cx26 under the spatial and temporal controls of the Cx30 gene regulatory mechanisms integrated in bacterial artificial chromosome. These genetically reconstituted GJs in Cx30-/- mice consisting of native or non-native mixings of wild type Cxs mainly affect intercellular biochemical couplings. Results obtained from the third series of experiments will further test our hypothesis in vivo. Design of any effective treatment for patients suffering from sensorineural hearing loss caused by Cx mutations depends on our understanding of the role Cxs play in the cochlea. With

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successful implementation of the specific aims proposed here, we hope to significantly advance our knowledge of intercellular communication mediated by GJs in the cochlea and improve our ability to help millions of deaf patients in the future. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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.40 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 nonsyndromic deafness, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type nonsyndromic deafness (or synonyms) into the search box, and click Go. The following is the type of output you can expect from PubMed for nonsyndromic deafness (hyperlinks lead to article summaries): •

A 3-nucleotide deletion in the polypyrimidine tract of intron 7 of the DFNA5 gene causes nonsyndromic hearing impairment in a Chinese family. Author(s): Yu C, Meng X, Zhang S, Zhao G, Hu L, Kong X. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14559215&query_hl=36&itool=pubmed_docsum

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A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. Author(s): del Castillo I, Villamar M, Moreno-Pelayo MA, del Castillo FJ, Alvarez A, Telleria D, Menendez I, Moreno F. Source: The New England Journal of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11807148&query_hl=36&itool=pubmed_docsum

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A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24. Author(s): Verhoeven K, Van Camp G, Govaerts PJ, Balemans W, Schatteman I, Verstreken M, Van Laer L, Smith RJ, Brown MR, Van de Heyning PH, Somers T, Offeciers FE, Willems PJ. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9150164&query_hl=37&itool=pubmed_docsum

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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 gene for fluctuating, progressive autosomal dominant nonsyndromic hearing loss, DFNA16, maps to chromosome 2q23-24.3. Author(s): Fukushima K, Kasai N, Ueki Y, Nishizaki K, Sugata K, Hirakawa S, Masuda A, Gunduz M, Ninomiya Y, Masuda Y, Sato M, McGuirt WT, Coucke P, Van Camp G, Smith RJ. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10364526&query_hl=37&itool=pubmed_docsum

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A human recessive neurosensory nonsyndromic hearing impairment locus is potential homologue of murine deafness (dn) locus. Author(s): Jain PK, Fukushima K, Deshmukh D, Ramesh A, Thomas E, Lalwani AK, Kumar S, Plopis B, Skarka H, Srisailapathy CR, et al. Source: Human Molecular Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8634715&query_hl=36&itool=pubmed_docsum

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A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3-q14.1. Author(s): Ramzan K, Shaikh RS, Ahmad J, Khan SN, Riazuddin S, Ahmed ZM, Friedman TB, Wilcox ER, Riazuddin S. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15538632&query_hl=34&itool=pubmed_docsum

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A new locus for nonsyndromic deafness DFNB51 maps to chromosome 11p13-p12. Author(s): Shaikh RS, Ramzan K, Nazli S, Sattar S, Khan SN, Riazuddin S, Ahmed ZM, Friedman TB, Riazuddin S. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16158433&query_hl=34&itool=pubmed_docsum

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A novel autosomal recessive nonsyndromic hearing impairment locus (DFNB42) maps to chromosome 3q13.31-q22.3. Author(s): Aslam M, Wajid M, Chahrour MH, Ansar M, Haque S, Pham TL, Santos RP, Yan K, Ahmad W, Leal SM. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15641023&query_hl=36&itool=pubmed_docsum

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A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred. Author(s): Salam AA, Hafner FM, Linder TE, Spillmann T, Schinzel AA, Leal SM. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10777717&query_hl=37&itool=pubmed_docsum

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A novel locus (DFNA24) for prelingual nonprogressive autosomal dominant nonsyndromic hearing loss maps to 4q35-qter in a large Swiss German kindred. Author(s): Hafner FM, Salam AA, Linder TE, Balmer D, Baumer A, Schinzel AA, Spillmann T, Leal SM. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10739769&query_hl=37&itool=pubmed_docsum

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A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to chromosome 3q28-29. Author(s): Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, del Castillo I, Chardenoux S, Armenta D, Lathrop M, Petit C, Moreno F. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12483295&query_hl=37&itool=pubmed_docsum

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A novel locus for autosomal dominant nonsyndromic hearing loss identified at 5q31.132 in a Chinese pedigree. Author(s): Xia J, Deng H, Feng Y, Zhang H, Pan Q, Dai H, Long Z, Tang B, Deng H, Chen Y, Zhang R, Zheng D, He Y, Xia K. Source: Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12522684&query_hl=37&itool=pubmed_docsum

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A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13, maps to chromosome 6p. Author(s): Brown MR, Tomek MS, Van Laer L, Smith S, Kenyon JB, Van Camp G, Smith RJ. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9382104&query_hl=37&itool=pubmed_docsum

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A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA50, maps to chromosome 7q32 between the DFNB17 and DFNB13 deafness loci. Author(s): Modamio-Hoybjor S, Moreno-Pelayo MA, Mencia A, del Castillo I, Chardenoux S, Morais D, Lathrop M, Petit C, Moreno F. Source: Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14757864&query_hl=37&itool=pubmed_docsum

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A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness. Author(s): Gonzalez JR, Wang W, Ballana E, Estivill X. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16941638&query_hl=34&itool=pubmed_docsum

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A sensorineural progressive autosomal recessive form of isolated deafness, DFNB13, maps to chromosome 7q34-q36. Author(s): Mustapha M, Chardenoux S, Nieder A, Salem N, Weissenbach J, el-Zir E, Loiselet J, Petit C. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9781028&query_hl=35&itool=pubmed_docsum

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A YAC contig and an EST map in the pericentromeric region of chromosome 13 surrounding the loci for neurosensory nonsyndromic deafness (DFNB1 and DFNA3) and limb-girdle muscular dystrophy type 2C (LGMD2C). Author(s): Guilford P, Dode C, Crozet F, Blanchard S, Chaib H, Levilliers J, Levi-Acobas F, Weil D, Weissenbach J, Cohen D, et al. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8530067&query_hl=34&itool=pubmed_docsum

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A yeast model for the study of human DFNA5, a gene mutated in nonsyndromic hearing impairment. Author(s): Gregan J, Van Laer L, Lieto LD, Van Camp G, Kearsey SE. Source: Biochimica Et Biophysica Acta. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12853124&query_hl=36&itool=pubmed_docsum

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Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Author(s): Wang A, Liang Y, Fridell RA, Probst FJ, Wilcox ER, Touchman JW, Morton CC, Morell RJ, Noben-Trauth K, Camper SA, Friedman TB. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9603736&query_hl=34&itool=pubmed_docsum

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Autosomal dominant nonsyndromic hearing impairment. Author(s): Van Laer L, McGuirt WT, Yang T, Smith RJ, Van Camp G. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10704191&query_hl=36&itool=pubmed_docsum

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Autosomal recessive nonsyndromic hearing loss. Author(s): Sundstrom RA, Van Laer L, Van Camp G, Smith RJ. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10704186&query_hl=37&itool=pubmed_docsum

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Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness. Author(s): Li X, Fischel-Ghodsian N, Schwartz F, Yan Q, Friedman RA, Guan MX. Source: Nucleic Acids Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14960712&query_hl=34&itool=pubmed_docsum

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CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Author(s): Astuto LM, Bork JM, Weston MD, Askew JW, Fields RR, Orten DJ, Ohliger SJ, Riazuddin S, Morell RJ, Khan S, Riazuddin S, Kremer H, van Hauwe P, Moller CG, Cremers CW, Ayuso C, Heckenlively JR, Rohrschneider K, Spandau U, Greenberg J, Ramesar R, Reardon W, Bitoun P, Millan J, Legge R, Friedman TB, Kimberling WJ. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12075507&query_hl=34&itool=pubmed_docsum

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Clinical and molecular analysis of a four-generation Chinese family with aminoglycoside-induced and nonsyndromic hearing loss associated with the mitochondrial 12S rRNA C1494T mutation. Author(s): Wang Q, Li QZ, Han D, Zhao Y, Zhao L, Qian Y, Yuan H, Li R, Zhai S, Young WY, Guan MX. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16380089&query_hl=37&itool=pubmed_docsum

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Clinical genetic study of 144 patients with nonsyndromic hearing loss. Author(s): Kokitsu-Nakata NM, Guion-Almeida ML, Richieri-Costa A. Source: American Journal of Audiology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15903134&query_hl=37&itool=pubmed_docsum

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Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss. Author(s): Erbe CB, Harris KC, Runge-Samuelson CL, Flanary VA, Wackym PA. Source: The Laryngoscope. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15064611&query_hl=37&itool=pubmed_docsum

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Connexin 26 mutations and nonsyndromic hearing impairment in northern Finland. Author(s): Lopponen T, Vaisanen ML, Luotonen M, Allinen M, Uusimaa J, Lindholm P, Maki-Torkko E, Vayrynen M, Lopponen H, Leisti J. Source: The Laryngoscope. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14520102&query_hl=36&itool=pubmed_docsum

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Connexin26 mutations associated with nonsyndromic hearing loss. Author(s): Park HJ, Hahn SH, Chun YM, Park K, Kim HN. Source: The Laryngoscope. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10983956&query_hl=37&itool=pubmed_docsum

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Contribution of connexin 26 mutations to nonsyndromic deafness in Ashkenazi patients and the variable phenotypic effect of the mutation 167delT. Author(s): Lerer I, Sagi M, Malamud E, Levi H, Raas-Rothschild A, Abeliovich D. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11074495&query_hl=34&itool=pubmed_docsum

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Cosegregation of the G7444A mutation in the mitochondrial COI/tRNA(Ser(UCN)) genes with the 12S rRNA A1555G mutation in a Chinese family with aminoglycosideinduced and nonsyndromic hearing loss. Author(s): Yuan H, Qian Y, Xu Y, Cao J, Bai L, Shen W, Ji F, Zhang X, Kang D, Mo JQ, Greinwald JH, Han D, Zhai S, Young WY, Guan MX. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16152638&query_hl=37&itool=pubmed_docsum

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Deafness genes for nonsyndromic hearing loss and current studies in China. Author(s): Xiao Z, Xie D. Source: Chinese Medical Journal. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12173596&query_hl=37&itool=pubmed_docsum

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Deletion of and novel missense mutation in POU3F4 in 2 families segregating X-linked nonsyndromic deafness. Author(s): Vore AP, Chang EH, Hoppe JE, Butler MG, Forrester S, Schneider MC, Smith LL, Burke DW, Campbell CA, Smith RJ. Source: Archives of Otolaryngology--Head & Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16365218&query_hl=34&itool=pubmed_docsum

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Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese. Author(s): Tsukamoto K, Suzuki H, Harada D, Namba A, Abe S, Usami S. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14508505&query_hl=37&itool=pubmed_docsum

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Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation. Author(s): Bykhovskaya Y, Shohat M, Ehrenman K, Johnson D, Hamon M, Cantor RM, Aouizerat B, Bu X, Rotter JI, Jaber L, Fischel-Ghodsian N. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9632174&query_hl=34&itool=pubmed_docsum

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Fine mapping of autosomal dominant nonsyndromic hearing impairment DFNA21 to chromosome 6p24.1-22.3. Author(s): de Brouwer AP, Kunst HP, Krebsova A, van Asseldonk K, Reis A, Snoeckx RL, Van Camp G, Cremers CW, Cremers FP, Kremer H. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16007628&query_hl=36&itool=pubmed_docsum

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Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss. Author(s): Kalay E, Karaguzel A, Caylan R, Heister A, Cremers FP, Cremers CW, Brunner HG, de Brouwer AP, Kremer H. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16287143&query_hl=37&itool=pubmed_docsum

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Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness. Author(s): Bruzzone R, Gomes D, Denoyelle E, Duval N, Perea J, Veronesi V, Weil D, Petit C, Gabellec MM, D'Andrea P, White TW. Source: Cell Communication & Adhesion. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12064630&query_hl=34&itool=pubmed_docsum

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Functional analysis of R75Q mutation in the gene coding for Connexin 26 identified in a family with nonsyndromic hearing loss. Author(s): Piazza V, Beltramello M, Menniti M, Colao E, Malatesta P, Argento R, Chiarella G, Gallo LV, Catalano M, Perrotti N, Mammano F, Cassandro E. Source: Clinical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15996214&query_hl=37&itool=pubmed_docsum

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Genetic causes of nonsyndromic hearing loss. Author(s): Skvorak Giersch AB, Morton CC. Source: Current Opinion in Pediatrics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10590915&query_hl=37&itool=pubmed_docsum

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High frequency of GJB2 gene mutations in Polish patients with prelingual nonsyndromic deafness. Author(s): Wiszniewski W, Sobieszczanska-Radoszewska L, Nowakowska-Szyrwinska E, Obersztyn E, Bal J. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11551103&query_hl=34&itool=pubmed_docsum

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Human connexin 30 (GJB6), a candidate gene for nonsyndromic hearing loss: molecular cloning, tissue-specific expression, and assignment to chromosome 13q12. Author(s): Kelley PM, Abe S, Askew JW, Smith SD, Usami S, Kimberling WJ. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10610709&query_hl=37&itool=pubmed_docsum

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Identification of CRYM as a candidate responsible for nonsyndromic deafness, through cDNA microarray analysis of human cochlear and vestibular tissues. Author(s): Abe S, Katagiri T, Saito-Hisaminato A, Usami S, Inoue Y, Tsunoda T, Nakamura Y. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12471561&query_hl=34&itool=pubmed_docsum

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Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. Author(s): Scott DA, Kraft ML, Carmi R, Ramesh A, Elbedour K, Yairi Y, Srisailapathy CR, Rosengren SS, Markham AF, Mueller RF, Lench NJ, Van Camp G, Smith RJ, Sheffield VC. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9600457&query_hl=37&itool=pubmed_docsum

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Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan. Author(s): Su CC, Yang JJ, Shieh JC, Su MC, Li SY. Source: Audiology & Neuro-Otology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=17033161&query_hl=34&itool=pubmed_docsum

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Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2. Author(s): Marres H, van Ewijk M, Huygen P, Kunst H, van Camp G, Coucke P, Willems P, Cremers C. Source: Archives of Otolaryngology--Head & Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9193215&query_hl=37&itool=pubmed_docsum

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Isolated deafness following recovery from neurologic injury and adult respiratory distress syndrome. A sequela of intercurrent aminoglycoside and diuretic use. Author(s): Lynn AM, Redding GJ, Morray JP, Tyler DC. Source: Am J Dis Child. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=3984969&query_hl=35&itool=pubmed_docsum

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Localization of a novel autosomal recessive nonsyndromic hearing impairment locus DFNB65 to chromosome 20q13.2-q13.32. Author(s): Tariq A, Santos RL, Khan MN, Lee K, Hassan MJ, Ahmad W, Leal SM. Source: Journal of Molecular Medicine (Berlin, Germany). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16596430&query_hl=36&itool=pubmed_docsum

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Localization of a novel gene for nonsyndromic hearing loss (DFNB17) to chromosome region 7q31. Author(s): Greinwald JH Jr, Wayne S, Chen AH, Scott DA, Zbar RI, Kraft ML, Prasad S, Ramesh A, Coucke P, Srisailapathy CR, Lovett M, Van Camp G, Smith RJ. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9674898&query_hl=37&itool=pubmed_docsum

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Making sense of nonsyndromic deafness. Author(s): Smith RJ, Huygen PL. Source: Archives of Otolaryngology--Head & Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12707186&query_hl=34&itool=pubmed_docsum

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Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26. Author(s): Mangino M, Flex E, Capon F, Sangiuolo F, Carraro E, Gualandi F, Mazzoli M, Martini A, Novelli G, Dallapiccola B. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11571554&query_hl=37&itool=pubmed_docsum

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Mapping of a new autosomal recessive nonsyndromic hearing loss locus (DFNB32) to chromosome 1p13.3-22.1. Author(s): Masmoudi S, Tlili A, Majava M, Ghorbel AM, Chardenoux S, Lemainque A, Zina ZB, Moala J, Mannikko M, Weil D, Lathrop M, Ala-Kokko L, Drira M, Petit C, Ayadi H. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12634867&query_hl=37&itool=pubmed_docsum

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Mapping of a novel autosomal recessive nonsyndromic deafness locus (DFNB46) to chromosome 18p11.32-p11.31. Author(s): Mir A, Ansar M, Chahrour MH, Pham TL, Wajid M, Haque S, Yan K, Ahmad W, Leal SM. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15637723&query_hl=34&itool=pubmed_docsum

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Mapping of the alpha-tectorin gene (TECTA) to mouse chromosome 9 and human chromosome 11: a candidate for human autosomal dominant nonsyndromic deafness. Author(s): Hughes DC, Legan PK, Steel KP, Richardson GP. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9503015&query_hl=34&itool=pubmed_docsum

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Mapping of the otogelin gene (OTGN) to mouse chromosome 7 and human chromosome 11p14.3: a candidate for human autosomal recessive nonsyndromic deafness DFNB18. Author(s): Cohen-Salmon M, Mattei MG, Petit C. Source: Mammalian Genome : Official Journal of the International Mammalian Genome Society. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10337628&query_hl=34&itool=pubmed_docsum

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Maternal origin of a de novo mutation of the connexin 26 gene resulting in recessive nonsyndromic deafness. Author(s): Shalev SA, Hujirat Y. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14735592&query_hl=34&itool=pubmed_docsum

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Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family. Author(s): Zhao H, Li R, Wang Q, Yan Q, Deng JH, Han D, Bai Y, Young WY, Guan MX. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14681830&query_hl=34&itool=pubmed_docsum

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Maternally inherited nonsyndromic hearing loss is associated with the T7511C mutation in the mitochondrial tRNASerUCN gene in a Japanese family. Author(s): Li R, Ishikawa K, Deng JH, Heman-Ackah S, Tamagawa Y, Yang L, Bai Y, Ichimura K, Guan MX. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15670746&query_hl=37&itool=pubmed_docsum

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Maternally inherited nonsyndromic hearing loss. Author(s): Friedman RA, Bykhovskaya Y, Sue CM, DiMauro S, Bradley R, FallisCunningham R, Paradies N, Pensak ML, Smith RJ, Groden J, Li XC, Fischel-Ghodsian N. Source: American Journal of Medical Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10340654&query_hl=37&itool=pubmed_docsum

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Mitochondrial DNA mutations in patients with postlingual, nonsyndromic hearing impairment. Author(s): Jacobs HT, Hutchin TP, Kappi T, Gillies G, Minkkinen K, Walker J, Thompson K, Rovio AT, Carella M, Melchionda S, Zelante L, Gasparini P, Pyykko I, Shah ZH, Zeviani M, Mueller RF. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15292920&query_hl=36&itool=pubmed_docsum

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Mitochondrial mutation associated with nonsyndromic deafness. Author(s): Fischel-Ghodsian N, Prezant TR, Fournier P, Stewart IA, Maw M. Source: American Journal of Otolaryngology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8572257&query_hl=34&itool=pubmed_docsum

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Mutational analysis of the mitochondrial 12S rRNA and tRNASer(UCN) genes in Tunisian patients with nonsyndromic hearing loss. Author(s): Mkaouar-Rebai E, Tlili A, Masmoudi S, Louhichi N, Charfeddine I, Ben Amor M, Lahmar I, Driss N, Drira M, Ayadi H, Fakhfakh F. Source: Biochemical and Biophysical Research Communications. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16406239&query_hl=37&itool=pubmed_docsum

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Mutational spectrum of the WFS1 gene in Wolfram syndrome, nonsyndromic hearing impairment, diabetes mellitus, and psychiatric disease. Author(s): Cryns K, Sivakumaran TA, Van den Ouweland JM, Pennings RJ, Cremers CW, Flothmann K, Young TL, Smith RJ, Lesperance MM, Van Camp G. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12955714&query_hl=36&itool=pubmed_docsum

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Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Author(s): Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, Nadol JB Jr, Miyamoto RT, Linthicum FH Jr, Lubianca Neto JF, Hudspeth AJ, Seidman CE, Morton CC, Seidman JG. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9806553&query_hl=34&itool=pubmed_docsum

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Mutations in a novel isoform of TRIOBP that encodes a filamentous-actin binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. Author(s): Shahin H, Walsh T, Sobe T, Abu Sa'ed J, Abu Rayan A, Lynch ED, Lee MK, Avraham KB, King MC, Kanaan M. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16385458&query_hl=37&itool=pubmed_docsum

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Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice. Author(s): Wilson SM, Householder DB, Coppola V, Tessarollo L, Fritzsch B, Lee EC, Goss D, Carlson GA, Copeland NG, Jenkins NA. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11386759&query_hl=37&itool=pubmed_docsum

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Mutations in the gene encoding KIAA1199 protein, an inner-ear protein expressed in Deiters' cells and the fibrocytes, as the cause of nonsyndromic hearing loss. Author(s): Abe S, Usami S, Nakamura Y. Source: Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14577002&query_hl=37&itool=pubmed_docsum

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Mutations in the lipoma HMGIC fusion partner-like 5 (LHFPL5) gene cause autosomal recessive nonsyndromic hearing loss. Author(s): Kalay E, Li Y, Uzumcu A, Uyguner O, Collin RW, Caylan R, Ulubil-Emiroglu M, Kersten FF, Hafiz G, van Wijk E, Kayserili H, Rohmann E, Wagenstaller J, Hoefsloot LH, Strom TM, Nurnberg G, Baserer N, den Hollander AI, Cremers FP, Cremers CW, Becker C, Brunner HG, Nurnberg P, Karaguzel A, Basaran S, Kubisch C, Kremer H, Wollnik B. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16752389&query_hl=37&itool=pubmed_docsum

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Mutations in the TMPRSS3 gene are a rare cause of childhood nonsyndromic deafness in Caucasian patients. Author(s): Wattenhofer M, Di Iorio MV, Rabionet R, Dougherty L, Pampanos A, Schwede T, Montserrat-Sentis B, Arbones ML, Iliades T, Pasquadibisceglie A, D'Amelio M, Alwan S, Rossier C, Dahl HH, Petersen MB, Estivill X, Gasparini P, Scott HS, Antonarakis SE. Source: Journal of Molecular Medicine (Berlin, Germany). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11907649&query_hl=34&itool=pubmed_docsum

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MYO1F as a candidate gene for nonsyndromic deafness, DFNB15. Author(s): Chen AH, Stephan DA, Hasson T, Fukushima K, Nelissen CM, Chen AF, Jun AI, Ramesh A, Van Camp G, Smith RJ. Source: Archives of Otolaryngology--Head & Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11493199&query_hl=34&itool=pubmed_docsum

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MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. Author(s): Melchionda S, Ahituv N, Bisceglia L, Sobe T, Glaser F, Rabionet R, Arbones ML, Notarangelo A, Di Iorio E, Carella M, Zelante L, Estivill X, Avraham KB, Gasparini P. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11468689&query_hl=37&itool=pubmed_docsum

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Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Author(s): Lynch ED, Lee MK, Morrow JE, Welcsh PL, Leon PE, King MC. Source: Science. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9360932&query_hl=34&itool=pubmed_docsum

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Nonsyndromic deafness. Author(s): Nance WE. Source: Birth Defects Orig Artic Ser. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=7011439&query_hl=34&itool=pubmed_docsum

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Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Author(s): Van Laer L, Huizing EH, Verstreken M, van Zuijlen D, Wauters JG, Bossuyt PJ, Van de Heyning P, McGuirt WT, Smith RJ, Willems PJ, Legan PK, Richardson GP, Van Camp G. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9771715&query_hl=36&itool=pubmed_docsum

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Nonsyndromic hearing impairment: unparalleled heterogeneity. Author(s): Van Camp G, Willems PJ, Smith RJ. Source: American Journal of Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9106521&query_hl=36&itool=pubmed_docsum

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Nonsyndromic hearing loss caused by a mitochondrial T7511C mutation. Author(s): Ishikawa K, Tamagawa Y, Takahashi K, Kimura H, Kusakari J, Hara A, Ichimura K. Source: The Laryngoscope. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12172268&query_hl=37&itool=pubmed_docsum

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Nonsyndromic hearing loss. Author(s): Van Laer L, Cryns K, Smith RJ, Van Camp G. Source: Ear and Hearing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12923419&query_hl=37&itool=pubmed_docsum

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Nonsyndromic hearing loss: an analysis of audiograms. Author(s): Liu X, Xu L. Source: The Annals of Otology, Rhinology, and Laryngology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8203808&query_hl=37&itool=pubmed_docsum

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Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment. Author(s): Santos RL, El-Shanti H, Sikandar S, Lee K, Bhatti A, Yan K, Chahrour MH, McArthur N, Pham TL, Mahasneh AA, Ahmad W, Leal SM. Source: Journal of Molecular Medicine (Berlin, Germany). http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16389551&query_hl=36&itool=pubmed_docsum

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Novel TMC1 structural and splice variants associated with congenital nonsyndromic deafness in a Sudanese pedigree. Author(s): Meyer CG, Gasmelseed NM, Mergani A, Magzoub MM, Muntau B, Thye T, Horstmann RD. Source: Human Mutation. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15605408&query_hl=34&itool=pubmed_docsum

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Passage to India: the search for genes causing autosomal recessive nonsyndromic hearing loss. Author(s): Zbar RI, Ramesh A, Srisailapathy CR, Fukushima K, Wayne S, Smith RJ. Source: Otolaryngology and Head and Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9527113&query_hl=37&itool=pubmed_docsum

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Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4. Author(s): Coyle B, Coffey R, Armour JA, Gausden E, Hochberg Z, Grossman A, Britton K, Pembrey M, Reardon W, Trembath R. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=8630497&query_hl=34&itool=pubmed_docsum

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Phenotype of DFNA11: a nonsyndromic hearing loss caused by a myosin VIIA mutation. Author(s): Tamagawa Y, Ishikawa K, Ishikawa K, Ishida T, Kitamura K, Makino S, Tsuru T, Ichimura K. Source: The Laryngoscope. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11889386&query_hl=37&itool=pubmed_docsum

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Potassium ion recycling pathway via gap junction systems in the mammalian cochlea and its interruption in hereditary nonsyndromic deafness. Author(s): Kikuchi T, Adams JC, Miyabe Y, So E, Kobayashi T. Source: Medical Electron Microscopy : Official Journal of the Clinical Electron Microscopy Society of Japan. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=11810458&query_hl=34&itool=pubmed_docsum

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Prelingual nonsyndromic hearing loss in Greece. Molecular and clinical findings. Author(s): Iliades T, Eleftheriades N, Iliadou V, Pampanos A, Voyiatzis N, Economides J, Leotsakos P, Neou P, Tsakanikos M, Antoniadi T, Konstantopoulou I, Yannoukakos D, Grigoriadou M, Skevas A, Petersen MB. Source: Orl; Journal for Oto-Rhino-Laryngology and Its Related Specialties. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=12417772&query_hl=37&itool=pubmed_docsum

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Presymptomatic diagnosis of nonsyndromic hearing loss by genotyping. Author(s): Chen AH, Mueller RF, Prasad SD, Greinwald JH Jr, Manaligod J, Muilenburg AC, Verhoeven K, Van Camp G, Smith RJ. Source: Archives of Otolaryngology--Head & Neck Surgery. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9440775&query_hl=37&itool=pubmed_docsum

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Prevalence of the 35delG mutation in the GJB2 gene of patients with nonsyndromic hearing loss from Croatia. Author(s): Sansovic I, Knezevic J, Matijevic T, Balen S, Barisic I, Pavelic J. Source: Genetic Testing. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16379542&query_hl=37&itool=pubmed_docsum

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Refined localization and two additional linked families for the DFNA10 locus for nonsyndromic hearing impairment. Author(s): Verhoeven K, Fagerheim T, Prasad S, Wayne S, De Clau F, Balemans W, Verstreken M, Schatteman I, Solem B, Van de Heyning P, Tranebjarg L, Smith RJ, Van Camp G. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10982027&query_hl=36&itool=pubmed_docsum

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Refined localization of autosomal recessive nonsyndromic deafness DFNB10 locus using 34 novel microsatellite markers, genomic structure, and exclusion of six known genes in the region. Author(s): Berry A, Scott HS, Kudoh J, Talior I, Korostishevsky M, Wattenhofer M, Guipponi M, Barras C, Rossier C, Shibuya K, Wang J, Kawasaki K, Asakawa S, Minoshima S, Shimizu N, Antonarakis S, Bonne-Tamir B. Source: Genomics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10950923&query_hl=34&itool=pubmed_docsum

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Screening for mutations in the GJB3 gene in Brazilian patients with nonsyndromic deafness. Author(s): Alexandrino F, Oliveira CA, Reis FC, Maciel-Guerra AT, Sartorato EL. Source: Journal of Applied Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15131355&query_hl=34&itool=pubmed_docsum

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SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. Author(s): Albert S, Blons H, Jonard L, Feldmann D, Chauvin P, Loundon N, SergentAllaoui A, Houang M, Joannard A, Schmerber S, Delobel B, Leman J, Journel H, Catros H, Dollfus H, Eliot MM, David A, Calais C, Drouin-Garraud V, Obstoy MF, Tran Ba Huy P, Lacombe D, Duriez F, Francannet C, Bitoun P, Petit C, Garabedian EN, Couderc R, Marlin S, Denoyelle F. Source: European Journal of Human Genetics : Ejhg. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16570074&query_hl=36&itool=pubmed_docsum

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The autosomal recessive isolated deafness, DFNB2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Author(s): Weil D, Kussel P, Blanchard S, Levy G, Levi-Acobas F, Drira M, Ayadi H, Petit C. Source: Nature Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=9171833&query_hl=35&itool=pubmed_docsum

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The genetic bases for syndromic and nonsyndromic deafness among Jews. Author(s): Ben-Yosef T, Friedman TB. Source: Trends in Molecular Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=14604828&query_hl=34&itool=pubmed_docsum

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The GJB2 mutation R75Q can cause nonsyndromic hearing loss DFNA3 or hereditary palmoplantar keratoderma with deafness. Author(s): Feldmann D, Denoyelle F, Blons H, Lyonnet S, Loundon N, Rouillon I, HadjRabia S, Petit C, Couderc R, Garabedian EN, Marlin S. Source: Am J Med Genet A. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=16059934&query_hl=37&itool=pubmed_docsum

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The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. Author(s): Sobe T, Vreugde S, Shahin H, Berlin M, Davis N, Kanaan M, Yaron Y, OrrUrtreger A, Frydman M, Shohat M, Avraham KB. Source: Human Genetics. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=10982182&query_hl=37&itool=pubmed_docsum

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The R245X mutation of PCDH15 in Ashkenazi Jewish children diagnosed with nonsyndromic hearing loss foreshadows retinitis pigmentosa. Author(s): Brownstein Z, Ben-Yosef T, Dagan O, Frydman M, Abeliovich D, Sagi M, Abraham FA, Taitelbaum-Swead R, Shohat M, Hildesheimer M, Friedman TB, Avraham KB. Source: Pediatric Research. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A bstractPlus&list_uids=15028842&query_hl=37&itool=pubmed_docsum

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APPENDICES

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APPENDIX A. HELP ME UNDERSTAND GENETICS Overview This appendix presents basic information about genetics in clear language and provides links to online resources.41

The Basics: Genes and How They Work This section gives you information on the basics of cells, DNA, genes, chromosomes, and proteins. What Is a Cell? Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. They provide structure for the body, take in nutrients from food, convert those nutrients into energy, and carry out specialized functions. Cells also contain the body’s hereditary material and can make copies of themselves. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell. Human cells contain the following major parts, listed in alphabetical order: •

Cytoplasm: The cytoplasm is fluid inside the cell that surrounds the organelles.

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Endoplasmic reticulum (ER): This organelle helps process molecules created by the cell and transport them to their specific destinations either inside or outside the cell.

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Golgi apparatus: The golgi apparatus packages molecules processed by the endoplasmic reticulum to be transported out of the cell.

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Lysosomes and peroxisomes: These organelles are the recycling center of the cell. They digest foreign bacteria that invade the cell, rid the cell of toxic substances, and recycle worn-out cell components.

41 This appendix is an excerpt from the National Library of Medicine’s handbook, Help Me Understand Genetics. For the full text of the Help Me Understand Genetics handbook, see http://ghr.nlm.nih.gov/handbook.

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Mitochondria: Mitochondria are complex organelles that convert energy from food into a form that the cell can use. They have their own genetic material, separate from the DNA in the nucleus, and can make copies of themselves.

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Nucleus: The nucleus serves as the cell’s command center, sending directions to the cell to grow, mature, divide, or die. It also houses DNA (deoxyribonucleic acid), the cell’s hereditary material. The nucleus is surrounded by a membrane called the nuclear envelope, which protects the DNA and separates the nucleus from the rest of the cell.

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Plasma membrane: The plasma membrane is the outer lining of the cell. It separates the cell from its environment and allows materials to enter and leave the cell.

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Ribosomes: Ribosomes are organelles that process the cell’s genetic instructions to create proteins. These organelles can float freely in the cytoplasm or be connected to the endoplasmic reticulum. What Is DNA?

DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA). The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T). Human DNA consists of about 3 billion bases, and more than 99 percent of those bases are the same in all people. The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences. DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar, and phosphate are called a nucleotide. Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder. An important property of DNA is that it can replicate, or make copies of itself. Each strand of DNA in the double helix can serve as a pattern for duplicating the sequence of bases. This is critical when cells divide because each new cell needs to have an exact copy of the DNA present in the old cell.

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DNA is a double helix formed by base pairs attached to a sugar-phosphate backbone. What Is Mitochondrial DNA? Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Each cell contains hundreds to thousands of mitochondria, which are located in the fluid that surrounds the nucleus (the cytoplasm). Mitochondria produce energy through a process called oxidative phosphorylation. This process uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell’s main energy source. A set of enzyme complexes, designated as complexes I-V, carry out oxidative phosphorylation within mitochondria. In addition to energy production, mitochondria play a role in several other cellular activities. For example, mitochondria help regulate the self-destruction of cells (apoptosis). They are also necessary for the production of substances such as cholesterol and heme (a component of hemoglobin, the molecule that carries oxygen in the blood). Mitochondrial DNA contains 37 genes, all of which are essential for normal mitochondrial function. Thirteen of these genes provide instructions for making enzymes involved in oxidative phosphorylation. The remaining genes provide instructions for making molecules called transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), which are chemical cousins of

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DNA. These types of RNA help assemble protein building blocks (amino acids) into functioning proteins. What Is a Gene? A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes. Every person has two copies of each gene, one inherited from each parent. Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

Genes are made up of DNA. Each chromosome contains many genes. What Is a Chromosome? In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled many times around proteins called histones that support its structure. Chromosomes are not visible in the cell’s nucleus—not even under a microscope—when the cell is not dividing. However, the DNA that makes up chromosomes becomes more tightly packed during cell division and is then visible under a microscope. Most of what researchers know about chromosomes was learned by observing chromosomes during cell division. Each chromosome has a constriction point called the centromere, which divides the chromosome into two sections, or “arms.” The short arm of the chromosome is labeled the “p arm.” The long arm of the chromosome is labeled the “q arm.” The location of the centromere on each chromosome gives the chromosome its characteristic shape, and can be used to help describe the location of specific genes.


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DNA and histone proteins are packaged into structures called chromosomes. How Many Chromosomes Do People Have? In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twentytwo of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.

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The 22 autosomes are numbered by size. The other two chromosomes, X and Y, are the sex chromosomes. This picture of the human chromosomes lined up in pairs is called a karyotype. How Do Geneticists Indicate the Location of a Gene? Geneticists use maps to describe the location of a particular gene on a chromosome. One type of map uses the cytogenetic location to describe a gene’s position. The cytogenetic location is based on a distinctive pattern of bands created when chromosomes are stained with certain chemicals. Another type of map uses the molecular location, a precise description of a gene’s position on a chromosome. The molecular location is based on the sequence of DNA building blocks (base pairs) that make up the chromosome. Cytogenetic Location Geneticists use a standardized way of describing a gene’s cytogenetic location. In most cases, the location describes the position of a particular band on a stained chromosome: 17q12 It can also be written as a range of bands, if less is known about the exact location: 17q12-q21 The combination of numbers and letters provide a gene’s “address” on a chromosome. This address is made up of several parts: •

The chromosome on which the gene can be found. The first number or letter used to describe a gene’s location represents the chromosome. Chromosomes 1 through 22 (the autosomes) are designated by their chromosome number. The sex chromosomes are designated by X or Y.


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•

The arm of the chromosome. Each chromosome is divided into two sections (arms) based on the location of a narrowing (constriction) called the centromere. By convention, the shorter arm is called p, and the longer arm is called q. The chromosome arm is the second part of the gene’s address. For example, 5q is the long arm of chromosome 5, and Xp is the short arm of the X chromosome.

•

The position of the gene on the p or q arm. The position of a gene is based on a distinctive pattern of light and dark bands that appear when the chromosome is stained in a certain way. The position is usually designated by two digits (representing a region and a band), which are sometimes followed by a decimal point and one or more additional digits (representing sub-bands within a light or dark area). The number indicating the gene position increases with distance from the centromere. For example: 14q21 represents position 21 on the long arm of chromosome 14. 14q21 is closer to the centromere than 14q22.

Sometimes, the abbreviations “cen” or “ter” are also used to describe a gene’s cytogenetic location. “Cen” indicates that the gene is very close to the centromere. For example, 16pcen refers to the short arm of chromosome 16 near the centromere. “Ter” stands for terminus, which indicates that the gene is very close to the end of the p or q arm. For example, 14qter refers to the tip of the long arm of chromosome 14. (“Tel” is also sometimes used to describe a gene’s location. “Tel” stands for telomeres, which are at the ends of each chromosome. The abbreviations “tel” and “ter” refer to the same location.)

The CFTR gene is located on the long arm of chromosome 7 at position 7q31.2.

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Molecular Location The Human Genome Project, an international research effort completed in 2003, determined the sequence of base pairs for each human chromosome. This sequence information allows researchers to provide a more specific address than the cytogenetic location for many genes. A gene’s molecular address pinpoints the location of that gene in terms of base pairs. For example, the molecular location of the APOE gene on chromosome 19 begins with base pair 50,100,901 and ends with base pair 50,104,488. This range describes the gene’s precise position on chromosome 19 and indicates the size of the gene (3,588 base pairs). Knowing a gene’s molecular location also allows researchers to determine exactly how far the gene is from other genes on the same chromosome. Different groups of researchers often present slightly different values for a gene’s molecular location. Researchers interpret the sequence of the human genome using a variety of methods, which can result in small differences in a gene’s molecular address. For example, the National Center for Biotechnology Information (NCBI) identifies the molecular location of the APOE gene as base pair 50,100,901 to base pair 50,104,488 on chromosome 19. The Ensembl database identifies the location of this gene as base pair 50,100,879 to base pair 50,104,489 on chromosome 19. Neither of these addresses is incorrect; they represent different interpretations of the same data. For consistency, Genetics Home Reference presents data from NCBI for the molecular location of genes. What Are Proteins and What Do They Do? Proteins are large, complex molecules that play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs. Proteins are made up of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different types of amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique 3-dimensional structure and its specific function.


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Examples of Protein Functions Proteins can be described according to their large range of functions in the body, listed in alphabetical order: Function Antibody

Description Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body.

Example Immunoglobulin G (IgG)

Enzyme

Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA.

Phenylalanine hydroxylase

Messenger

Messenger proteins, such as some types of hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs.

Growth hormone

Structural component

These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. These proteins bind and carry atoms and small molecules within cells and throughout the body.

Actin

Transport/storage

Ferritin

How Does a Gene Make a Protein? Most genes contain the information needed to make functional molecules called proteins. (A few genes produce other molecules that help the cell assemble proteins.) The journey from gene to protein is complex and tightly controlled within each cell. It consists of two major steps: transcription and translation. Together, transcription and translation are known as gene expression. During the process of transcription, the information stored in a gene’s DNA is transferred to a similar molecule called RNA (ribonucleic acid) in the cell nucleus. Both RNA and DNA are made up of a chain of nucleotide bases, but they have slightly different chemical properties. The type of RNA that contains the information for making a protein is called messenger RNA (mRNA) because it carries the information, or message, from the DNA out of the nucleus into the cytoplasm. Translation, the second step in getting from a gene to a protein, takes place in the cytoplasm. The mRNA interacts with a specialized complex called a ribosome, which “reads” the sequence of mRNA bases. Each sequence of three bases, called a codon, usually codes for

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one particular amino acid. (Amino acids are the building blocks of proteins.) A type of RNA called transfer RNA (tRNA) assembles the protein, one amino acid at a time. Protein assembly continues until the ribosome encounters a “stop” codon (a sequence of three bases that does not code for an amino acid). The flow of information from DNA to RNA to proteins is one of the fundamental principles of molecular biology. It is so important that it is sometimes called the “central dogma.”

Through the processes of transcription and translation, information from genes is used to make proteins.

Can Genes Be Turned On and Off in Cells? Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood. Gene regulation can occur at any point during gene expression, but most commonly occurs at the level of transcription (when the information in a gene’s DNA is transferred to mRNA). Signals from the environment or from other cells activate proteins called transcription factors. These proteins bind to regulatory regions of a gene and increase or decrease the level of transcription. By controlling the level of transcription, this process can determine the amount of protein product that is made by a gene at any given time.


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How Do Cells Divide? There are two types of cell division: mitosis and meiosis. Most of the time when people refer to “cell division,” they mean mitosis, the process of making new body cells. Meiosis is the type of cell division that creates egg and sperm cells. Mitosis is a fundamental process for life. During mitosis, a cell duplicates all of its contents, including its chromosomes, and splits to form two identical daughter cells. Because this process is so critical, the steps of mitosis are carefully controlled by a number of genes. When mitosis is not regulated correctly, health problems such as cancer can result. The other type of cell division, meiosis, ensures that humans have the same number of chromosomes in each generation. It is a two-step process that reduces the chromosome number by half—from 46 to 23—to form sperm and egg cells. When the sperm and egg cells unite at conception, each contributes 23 chromosomes so the resulting embryo will have the usual 46. Meiosis also allows genetic variation through a process of DNA shuffling while the cells are dividing.

Mitosis and meiosis, the two types of cell division. How Do Genes Control the Growth and Division of Cells? A variety of genes are involved in the control of cell growth and division. The cell cycle is the cell’s way of replicating itself in an organized, step-by-step fashion. Tight regulation of this process ensures that a dividing cell’s DNA is copied properly, any errors in the DNA are repaired, and each daughter cell receives a full set of chromosomes. The cycle has checkpoints (also called restriction points), which allow certain genes to check for mistakes and halt the cycle for repairs if something goes wrong.

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If a cell has an error in its DNA that cannot be repaired, it may undergo programmed cell death (apoptosis). Apoptosis is a common process throughout life that helps the body get rid of cells it doesn’t need. Cells that undergo apoptosis break apart and are recycled by a type of white blood cell called a macrophage. Apoptosis protects the body by removing genetically damaged cells that could lead to cancer, and it plays an important role in the development of the embryo and the maintenance of adult tissues. Cancer results from a disruption of the normal regulation of the cell cycle. When the cycle proceeds without control, cells can divide without order and accumulate genetic defects that can lead to a cancerous tumor.

Genetic Mutations and Health This section presents basic information about gene mutations, chromosomal changes, and conditions that run in families.42 What Is a Gene Mutation and How Do Mutations Occur? A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome. Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person’s lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person’s life in virtually every cell in the body. Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder. Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person’s life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation. Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism. Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are 42

This section has been adapted from the National Library of Medicine’s handbook, Help Me Understand Genetics, which presents basic information about genetics in clear language and provides links to online resources: http://ghr.nlm.nih.gov/handbook.


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responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders. How Can Gene Mutations Affect Health and Development? To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene’s instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder. In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life. It is important to note that genes themselves do not cause disease—genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has “the cystic fibrosis gene,” they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene. Do All Gene Mutations Affect Health and Development? No, only a small percentage of mutations cause genetic disorders—most have no impact on health or development. For example, some mutations alter a gene’s DNA base sequence but do not change the function of the protein made by the gene. Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease. A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria. For More Information about DNA Repair and the Health Effects of Gene Mutations •

The University of Utah Genetic Science Learning Center provides information about genetic disorders that explains why some mutations cause disorders but others do not. (Refer to the questions in the far right column.) See http://learn.genetics.utah.edu/units/disorders/whataregd/.

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Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called “What Is A Cell?”, scroll down to the heading “DNA Repair Mechanisms.” See http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html. What Kinds of Gene Mutations Are Possible?

The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include: •

Missense mutation: This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.

•

Nonsense mutation: A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.

•

Insertion: An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.

•

Deletion: A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).

•

Duplication: A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.

•

Frameshift mutation: This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.

•

Repeat expansion: Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly. Can Changes in Chromosomes Affect Health and Development?

Changes that affect entire chromosomes or segments of chromosomes can cause problems with growth, development, and function of the body’s systems. These changes can affect many genes along the chromosome and alter the proteins made by those genes. Conditions caused by a change in the number or structure of chromosomes are known as chromosomal disorders. Human cells normally contain 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. A change in the number of chromosomes leads to a chromosomal disorder. These changes can occur during the formation of reproductive cells (eggs and sperm) or in early fetal development. A gain or loss of chromosomes from the normal 46 is called aneuploidy.


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The most common form of aneuploidy is trisomy, or the presence of an extra chromosome in each cell. “Tri-” is Greek for “three”; people with trisomy have three copies of a particular chromosome in each cell instead of the normal two copies. Down syndrome is an example of a condition caused by trisomy—people with Down syndrome typically have three copies of chromosome 21 in each cell, for a total of 47 chromosomes per cell. Monosomy, or the loss of one chromosome from each cell, is another kind of aneuploidy. “Mono-” is Greek for “one”; people with monosomy have one copy of a particular chromosome in each cell instead of the normal two copies. Turner syndrome is a condition caused by monosomy. Women with Turner syndrome are often missing one copy of the X chromosome in every cell, for a total of 45 chromosomes per cell. Chromosomal disorders can also be caused by changes in chromosome structure. These changes are caused by the breakage and reunion of chromosome segments when an egg or sperm cell is formed or in early fetal development. Pieces of DNA can be rearranged within one chromosome, or transferred between two or more chromosomes. The effects of structural changes depend on their size and location. Many different structural changes are possible; some cause medical problems, while others may have no effect on a person’s health. Many cancer cells also have changes in their chromosome number or structure. These changes most often occur in somatic cells (cells other than eggs and sperm) during a person’s lifetime. Can Changes in Mitochondrial DNA Affect Health and Development? Mitochondria are structures within cells that convert the energy from food into a form that cells can use. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA (known as mitochondrial DNA or mtDNA). In some cases, inherited changes in mitochondrial DNA can cause problems with growth, development, and function of the body’s systems. These mutations disrupt the mitochondria’s ability to generate energy efficiently for the cell. Conditions caused by mutations in mitochondrial DNA often involve multiple organ systems. The effects of these conditions are most pronounced in organs and tissues that require a lot of energy (such as the heart, brain, and muscles). Although the health consequences of inherited mitochondrial DNA mutations vary widely, frequently observed features include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, loss of intellectual functions (dementia), hearing loss, and abnormalities involving the eyes and vision. Mitochondrial DNA is also prone to noninherited (somatic) mutations. Somatic mutations occur in the DNA of certain cells during a person’s lifetime, and typically are not passed to future generations. Because mitochondrial DNA has a limited ability to repair itself when it is damaged, these mutations tend to build up over time. A buildup of somatic mutations in mitochondrial DNA has been associated with some forms of cancer and an increased risk of certain age-related disorders such as heart disease, Alzheimer disease, and Parkinson disease. Additionally, research suggests that the progressive accumulation of these mutations over a person’s lifetime may play a role in the normal process of aging.

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What Are Complex or Multifactorial Disorders? Researchers are learning that nearly all conditions and diseases have a genetic component. Some disorders, such as sickle cell anemia and cystic fibrosis, are caused by mutations in a single gene. The causes of many other disorders, however, are much more complex. Common medical problems such as heart disease, diabetes, and obesity do not have a single genetic cause—they are likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. Conditions caused by many contributing factors are called complex or multifactorial disorders. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person’s risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. By 2010, however, researchers predict they will have found the major contributing genes for many common complex disorders. What Information about a Genetic Condition Can Statistics Provide? Statistical data can provide general information about how common a condition is, how many people have the condition, or how likely it is that a person will develop the condition. Statistics are not personalized, however—they offer estimates based on groups of people. By taking into account a person’s family history, medical history, and other factors, a genetics professional can help interpret what statistics mean for a particular patient. Common Statistical Terms Some statistical terms are commonly used when describing genetic conditions and other disorders. These terms include: Statistical Term Incidence

Description The incidence of a gene mutation or a genetic disorder is the number of people who are born with the mutation or disorder in a specified group per year. Incidence is often written in the form “1 in [a number]” or as a total number of live births.

Examples About 1 in 200,000 people in the United States are born with syndrome A each year. An estimated 15,000 infants with syndrome B were born last year worldwide.


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Prevalence

The prevalence of a gene mutation or a genetic disorder is the total number of people in a specified group at a given time who have the mutation or disorder. This term includes both newly diagnosed and preexisting cases in people of any age. Prevalence is often written in the form “1 in [a number]” or as a total number of people who have a condition.

Approximately 1 in 100,000 people in the United States have syndrome A at the present time. About 100,000 children worldwide currently have syndrome B.

Mortality

Mortality is the number of deaths from a particular disorder occurring in a specified group per year. Mortality is usually expressed as a total number of deaths.

An estimated 12,000 people worldwide died from syndrome C in 2002.

Lifetime risk

Lifetime risk is the average risk of developing a particular disorder at some point during a lifetime. Lifetime risk is often written as a percentage or as “1 in [a number].” It is important to remember that the risk per year or per decade is much lower than the lifetime risk. In addition, other factors may increase or decrease a person’s risk as compared with the average.

Approximately 1 percent of people in the United States develop disorder D during their lifetimes. The lifetime risk of developing disorder D is 1 in 100.

Naming Genetic Conditions Genetic conditions are not named in one standard way (unlike genes, which are given an official name and symbol by a formal committee). Doctors who treat families with a particular disorder are often the first to propose a name for the condition. Expert working groups may later revise the name to improve its usefulness. Naming is important because it allows accurate and effective communication about particular conditions, which will ultimately help researchers find new approaches to treatment. Disorder names are often derived from one or a combination of sources: •

The basic genetic or biochemical defect that causes the condition (for example, alpha-1 antitrypsin deficiency)

•

One or more major signs or symptoms of the disorder (for example, sickle cell anemia)

•

The parts of the body affected by the condition (for example, retinoblastoma)

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•

The name of a physician or researcher, often the first person to describe the disorder (for example, Marfan syndrome, which was named after Dr. Antoine Bernard-Jean Marfan)

•

A geographic area (for example, familial Mediterranean fever, which occurs mainly in populations bordering the Mediterranean Sea)

•

The name of a patient or family with the condition (for example, amyotrophic lateral sclerosis, which is also called Lou Gehrig disease after a famous baseball player who had the condition).

Disorders named after a specific person or place are called eponyms. There is debate as to whether the possessive form (e.g., Alzheimer’s disease) or the nonpossessive form (Alzheimer disease) of eponyms is preferred. As a rule, medical geneticists use the nonpossessive form, and this form may become the standard for doctors in all fields of medicine. Genetics Home Reference uses the nonpossessive form of eponyms. Genetics Home Reference consults with experts in the field of medical genetics to provide the current, most accurate name for each disorder. Alternate names are included as synonyms. Naming genes The HUGO Gene Nomenclature Committee (HGNC) designates an official name and symbol (an abbreviation of the name) for each known human gene. Some official gene names include additional information in parentheses, such as related genetic conditions, subtypes of a condition, or inheritance pattern. The HGNC is a non-profit organization funded by the U.K. Medical Research Council and the U.S. National Institutes of Health. The Committee has named more than 13,000 of the estimated 20,000 to 25,000 genes in the human genome. During the research process, genes often acquire several alternate names and symbols. Different researchers investigating the same gene may each give the gene a different name, which can cause confusion. The HGNC assigns a unique name and symbol to each human gene, which allows effective organization of genes in large databanks, aiding the advancement of research. For specific information about how genes are named, refer to the HGNC’s Guidelines for Human Gene Nomenclature. Genetics Home Reference describes genes using the HGNC’s official gene names and gene symbols. Genetics Home Reference frequently presents the symbol and name separated with a colon (for example, FGFR4: Fibroblast growth factor receptor 4).

Inheriting Genetic Conditions This section gives you information on inheritance patterns and understanding risk. What Does It Mean If a Disorder Seems to Run in My Family? A particular disorder might be described as “running in a family” if more than one person in the family has the condition. Some disorders that affect multiple family members are caused by gene mutations, which can be inherited (passed down from parent to child). Other conditions that appear to run in families are not inherited. Instead, environmental factors


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such as dietary habits or a combination of genetic and environmental factors are responsible for these disorders. It is not always easy to determine whether a condition in a family is inherited. A genetics professional can use a person’s family history (a record of health information about a person’s immediate and extended family) to help determine whether a disorder has a genetic component.

Some disorders are seen in more than one generation of a family. Why Is It Important to Know My Family Medical History? A family medical history is a record of health information about a person and his or her close relatives. A complete record includes information from three generations of relatives,

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including children, brothers and sisters, parents, aunts and uncles, nieces and nephews, grandparents, and cousins. Families have many factors in common, including their genes, environment, and lifestyle. Together, these factors can give clues to medical conditions that may run in a family. By noticing patterns of disorders among relatives, healthcare professionals can determine whether an individual, other family members, or future generations may be at an increased risk of developing a particular condition. A family medical history can identify people with a higher-than-usual chance of having common disorders, such as heart disease, high blood pressure, stroke, certain cancers, and diabetes. These complex disorders are influenced by a combination of genetic factors, environmental conditions, and lifestyle choices. A family history also can provide information about the risk of rarer conditions caused by mutations in a single gene, such as cystic fibrosis and sickle cell anemia. While a family medical history provides information about the risk of specific health concerns, having relatives with a medical condition does not mean that an individual will definitely develop that condition. On the other hand, a person with no family history of a disorder may still be at risk of developing that disorder. Knowing one’s family medical history allows a person to take steps to reduce his or her risk. For people at an increased risk of certain cancers, healthcare professionals may recommend more frequent screening (such as mammography or colonoscopy) starting at an earlier age. Healthcare providers may also encourage regular checkups or testing for people with a medical condition that runs in their family. Additionally, lifestyle changes such as adopting a healthier diet, getting regular exercise, and quitting smoking help many people lower their chances of developing heart disease and other common illnesses. The easiest way to get information about family medical history is to talk to relatives about their health. Have they had any medical problems, and when did they occur? A family gathering could be a good time to discuss these issues. Additionally, obtaining medical records and other documents (such as obituaries and death certificates) can help complete a family medical history. It is important to keep this information up-to-date and to share it with a healthcare professional regularly. What Are the Different Ways in which a Genetic Condition Can Be Inherited? Some genetic conditions are caused by mutations in a single gene. These conditions are usually inherited in one of several straightforward patterns, depending on the gene involved: Inheritance Pattern Autosomal dominant

Description One mutated copy of the gene in each cell is sufficient for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. Autosomal dominant disorders tend to occur in every generation of an affected family.

Examples Huntington disease, neurofibromatosis type 1


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Autosomal recessive

Two mutated copies of the gene are present in each cell when a person has an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family.

cystic fibrosis, sickle cell anemia

X-linked dominant

X-linked dominant disorders are caused by mutations in genes on the X chromosome. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women. Families with an X-linked dominant disorder often have both affected males and affected females in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

fragile X syndrome

X-linked recessive

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission).

hemophilia, Fabry disease

Codominant

In codominant inheritance, two different versions (alleles) of a gene can be expressed, and each version makes a slightly different protein. Both alleles influence the genetic trait or determine the characteristics of the genetic condition.

ABO blood group, alpha-1 antitrypsin deficiency

Mitochondrial

This type of inheritance, also known as maternal inheritance, applies to genes in mitochondrial DNA. Mitochondria, which are structures in each cell that convert molecules into energy, each contain a small amount of DNA. Because only egg cells contribute mitochondria to the developing embryo, only females can pass on mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children.

Leber hereditary optic neuropathy (LHON)

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Many other disorders are caused by a combination of the effects of multiple genes or by interactions between genes and the environment. Such disorders are more difficult to analyze because their genetic causes are often unclear, and they do not follow the patterns of inheritance described above. Examples of conditions caused by multiple genes or gene/environment interactions include heart disease, diabetes, schizophrenia, and certain types of cancer. Disorders caused by changes in the number or structure of chromosomes do not follow the straightforward patterns of inheritance listed above. Other genetic factors can also influence how a disorder is inherited. If a Genetic Disorder Runs in My Family, What Are the Chances That My Children Will Have the Condition? When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. This can be difficult to predict in some cases because many factors influence a person’s chances of developing a genetic condition. One important factor is how the condition is inherited. For example: •

Autosomal dominant inheritance: A person affected by an autosomal dominant disorder has a 50 percent chance of passing the mutated gene to each child. The chance that a child will not inherit the mutated gene is also 50 percent.

•

Autosomal recessive inheritance: Two unaffected people who each carry one copy of the mutated gene for an autosomal recessive disorder (carriers) have a 25 percent chance with each pregnancy of having a child affected by the disorder. The chance with each pregnancy of having an unaffected child who is a carrier of the disorder is 50 percent, and the chance that a child will not have the disorder and will not be a carrier is 25 percent.

•

X-linked dominant inheritance: The chance of passing on an X-linked dominant condition differs between men and women because men have one X chromosome and one Y chromosome, while women have two X chromosomes. A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. Therefore, the sons of a man with an X-linked dominant disorder will not be affected, but all of his daughters will inherit the condition. A woman passes on one or the other of her X chromosomes to each child. Therefore, a woman with an X-linked dominant disorder has a 50 percent chance of having an affected daughter or son with each pregnancy.

•

X-linked recessive inheritance: Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder also differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50 percent chance of having sons who are affected and a 50 percent chance of having daughters who carry one copy of the mutated gene.

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Codominant inheritance: In codominant inheritance, each parent contributes a different version of a particular gene, and both versions influence the resulting genetic trait. The chance of developing a genetic condition with codominant inheritance, and the characteristic features of that condition, depend on which versions of the gene are passed from parents to their child.

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Mitochondrial inheritance: Mitochondria, which are the energy-producing centers inside cells, each contain a small amount of DNA. Disorders with mitochondrial inheritance result from mutations in mitochondrial DNA. Although mitochondrial


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disorders can affect both males and females, only females can pass mutations in mitochondrial DNA to their children. A woman with a disorder caused by changes in mitochondrial DNA will pass the mutation to all of her daughters and sons, but the children of a man with such a disorder will not inherit the mutation. It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). Having one child with a disorder does not “protect” future children from inheriting the condition. Conversely, having a child without the condition does not mean that future children will definitely be affected. Although the chances of inheriting a genetic condition appear straightforward, factors such as a person’s family history and the results of genetic testing can sometimes modify those chances. In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. Estimating the chance of developing or passing on a genetic disorder can be complex. Genetics professionals can help people understand these chances and help them make informed decisions about their health. Factors that Influence the Effects of Particular Genetic Changes Reduced penetrance and variable expressivity are factors that influence the effects of particular genetic changes. These factors usually affect disorders that have an autosomal dominant pattern of inheritance, although they are occasionally seen in disorders with an autosomal recessive inheritance pattern. Reduced Penetrance Penetrance refers to the proportion of people with a particular genetic change (such as a mutation in a specific gene) who exhibit signs and symptoms of a genetic disorder. If some people with the mutation do not develop features of the disorder, the condition is said to have reduced (or incomplete) penetrance. Reduced penetrance often occurs with familial cancer syndromes. For example, many people with a mutation in the BRCA1 or BRCA2 gene will develop cancer during their lifetime, but some people will not. Doctors cannot predict which people with these mutations will develop cancer or when the tumors will develop. Reduced penetrance probably results from a combination of genetic, environmental, and lifestyle factors, many of which are unknown. This phenomenon can make it challenging for genetics professionals to interpret a person’s family medical history and predict the risk of passing a genetic condition to future generations. Variable Expressivity Although some genetic disorders exhibit little variation, most have signs and symptoms that differ among affected individuals. Variable expressivity refers to the range of signs and

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symptoms that can occur in different people with the same genetic condition. For example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience lifethreatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a mutation in the same gene (FBN1). As with reduced penetrance, variable expressivity is probably caused by a combination of genetic, environmental, and lifestyle factors, most of which have not been identified. If a genetic condition has highly variable signs and symptoms, it may be challenging to diagnose. What Do Geneticists Mean by Anticipation? The signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next. This phenomenon is called anticipation. Anticipation is most often seen with certain genetic disorders of the nervous system, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. Anticipation typically occurs with disorders that are caused by an unusual type of mutation called a trinucleotide repeat expansion. A trinucleotide repeat is a sequence of three DNA building blocks (nucleotides) that is repeated a number of times in a row. DNA segments with an abnormal number of these repeats are unstable and prone to errors during cell division. The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation. Most genetic disorders have signs and symptoms that differ among affected individuals, including affected people in the same family. Not all of these differences can be explained by anticipation. A combination of genetic, environmental, and lifestyle factors is probably responsible for the variability, although many of these factors have not been identified. Researchers study multiple generations of affected family members and consider the genetic cause of a disorder before determining that it shows anticipation. What Is Genomic Imprinting? Genomic imprinting is a factor that influences how some genetic conditions are inherited. People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting. In genes that undergo genomic imprinting, the parent of origin is often marked, or “stamped,” on the gene during the formation of egg and sperm cells. This stamping process, called methylation, is a chemical reaction that attaches small molecules called methyl groups to certain segments of DNA. These molecules identify which copy of a gene was inherited


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from the mother and which was inherited from the father. The addition and removal of methyl groups can be used to control the activity of genes. Only a small percentage of all human genes undergo genomic imprinting. Researchers are not yet certain why some genes are imprinted and others are not. They do know that imprinted genes tend to cluster together in the same regions of chromosomes. Two major clusters of imprinted genes have been identified in humans, one on the short (p) arm of chromosome 11 (at position 11p15) and another on the long (q) arm of chromosome 15 (in the region 15q11 to 15q13). What Is Uniparental Disomy? Uniparental disomy is a factor that influences how some genetic conditions are inherited. Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. In many cases, UPD likely has no effect on health or development. Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited from a person’s mother or father. A person with UPD may lack any active copies of essential genes that undergo genomic imprinting. This loss of gene function can lead to delayed development, mental retardation, or other medical problems. Several genetic disorders can result from UPD or a disruption of normal genomic imprinting. The most well-known conditions include Prader-Willi syndrome, which is characterized by uncontrolled eating and obesity, and Angelman syndrome, which causes mental retardation and impaired speech. Both of these disorders can be caused by UPD or other errors in imprinting involving genes on the long arm of chromosome 15. Other conditions, such as Beckwith-Wiedemann syndrome (a disorder characterized by accelerated growth and an increased risk of cancerous tumors), are associated with abnormalities of imprinted genes on the short arm of chromosome 11. Are Chromosomal Disorders Inherited? Although it is possible to inherit some types of chromosomal abnormalities, most chromosomal disorders (such as Down syndrome and Turner syndrome) are not passed from one generation to the next. Some chromosomal conditions are caused by changes in the number of chromosomes. These changes are not inherited, but occur as random events during the formation of reproductive cells (eggs and sperm). An error in cell division called nondisjunction results in reproductive cells with an abnormal number of chromosomes. For example, a reproductive cell may accidentally gain or lose one copy of a chromosome. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra or missing chromosome in each of the body’s cells.

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Changes in chromosome structure can also cause chromosomal disorders. Some changes in chromosome structure can be inherited, while others occur as random accidents during the formation of reproductive cells or in early fetal development. Because the inheritance of these changes can be complex, people concerned about this type of chromosomal abnormality may want to talk with a genetics professional. Some cancer cells also have changes in the number or structure of their chromosomes. Because these changes occur in somatic cells (cells other than eggs and sperm), they cannot be passed from one generation to the next. Why Are Some Genetic Conditions More Common in Particular Ethnic Groups? Some genetic disorders are more likely to occur among people who trace their ancestry to a particular geographic area. People in an ethnic group often share certain versions of their genes, which have been passed down from common ancestors. If one of these shared genes contains a disease-causing mutation, a particular genetic disorder may be more frequently seen in the group. Examples of genetic conditions that are more common in particular ethnic groups are sickle cell anemia, which is more common in people of African, African-American, or Mediterranean heritage; and Tay-Sachs disease, which is more likely to occur among people of Ashkenazi (eastern and central European) Jewish or French Canadian ancestry. It is important to note, however, that these disorders can occur in any ethnic group.

Genetic Consultation This section presents information on finding and visiting a genetic counselor or other genetics professional. What Is a Genetic Consultation? A genetic consultation is a health service that provides information and support to people who have, or may be at risk for, genetic disorders. During a consultation, a genetics professional meets with an individual or family to discuss genetic risks or to diagnose, confirm, or rule out a genetic condition. Genetics professionals include medical geneticists (doctors who specialize in genetics) and genetic counselors (certified healthcare workers with experience in medical genetics and counseling). Other healthcare professionals such as nurses, psychologists, and social workers trained in genetics can also provide genetic consultations. Consultations usually take place in a doctor’s office, hospital, genetics center, or other type of medical center. These meetings are most often in-person visits with individuals or families, but they are occasionally conducted in a group or over the telephone.


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Why Might Someone Have a Genetic Consultation? Individuals or families who are concerned about an inherited condition may benefit from a genetic consultation. The reasons that a person might be referred to a genetic counselor, medical geneticist, or other genetics professional include: •

A personal or family history of a genetic condition, birth defect, chromosomal disorder, or hereditary cancer.

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Two or more pregnancy losses (miscarriages), a stillbirth, or a baby who died.

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A child with a known inherited disorder, a birth defect, mental retardation, or developmental delay.

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A woman who is pregnant or plans to become pregnant at or after age 35. (Some chromosomal disorders occur more frequently in children born to older women.)

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Abnormal test results that suggest a genetic or chromosomal condition.

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An increased risk of developing or passing on a particular genetic disorder on the basis of a person’s ethnic background.

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People related by blood (for example, cousins) who plan to have children together. (A child whose parents are related may be at an increased risk of inheriting certain genetic disorders.)

A genetic consultation is also an important part of the decision-making process for genetic testing. A visit with a genetics professional may be helpful even if testing is not available for a specific condition, however. What Happens during a Genetic Consultation? A genetic consultation provides information, offers support, and addresses a patient’s specific questions and concerns. To help determine whether a condition has a genetic component, a genetics professional asks about a person’s medical history and takes a detailed family history (a record of health information about a person’s immediate and extended family). The genetics professional may also perform a physical examination and recommend appropriate tests. If a person is diagnosed with a genetic condition, the genetics professional provides information about the diagnosis, how the condition is inherited, the chance of passing the condition to future generations, and the options for testing and treatment. During a consultation, a genetics professional will: •

Interpret and communicate complex medical information.

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Help each person make informed, independent decisions about their health care and reproductive options.

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Respect each person’s individual beliefs, traditions, and feelings.

A genetics professional will NOT: •

Tell a person which decision to make.

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Advise a couple not to have children.

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Recommend that a woman continue or end a pregnancy.

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Tell someone whether to undergo testing for a genetic disorder. How Can I Find a Genetics Professional in My Area?

To find a genetics professional in your community, you may wish to ask your doctor for a referral. If you have health insurance, you can also contact your insurance company to find a medical geneticist or genetic counselor in your area who participates in your plan. Several resources for locating a genetics professional in your community are available online: •

GeneTests from the University of Washington provides a list of genetics clinics around the United States and international genetics clinics. You can also access the list by clicking on “Clinic Directory” at the top of the GeneTests home page. Clinics can be chosen by state or country, by service, and/or by specialty. State maps can help you locate a clinic in your area. See http://www.genetests.org/.

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The National Society of Genetic Counselors offers a searchable directory of genetic counselors in the United States. You can search by location, name, area of practice/specialization, and/or ZIP Code. See http://www.nsgc.org/resourcelink.cfm.

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The National Cancer Institute provides a Cancer Genetics Services Directory, which lists professionals who provide services related to cancer genetics. You can search by type of cancer or syndrome, location, and/or provider name at the following Web site: http://cancer.gov/search/genetics_services/.

Genetic Testing This section presents information on the benefits, costs, risks, and limitations of genetic testing. What Is Genetic Testing? Genetic testing is a type of medical test that identifies changes in chromosomes, genes, or proteins. Most of the time, testing is used to find changes that are associated with inherited disorders. The results of a genetic test can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Several hundred genetic tests are currently in use, and more are being developed. Genetic testing is voluntary. Because testing has both benefits and limitations, the decision about whether to be tested is a personal and complex one. A genetic counselor can help by providing information about the pros and cons of the test and discussing the social and emotional aspects of testing. What Are the Types of Genetic Tests? Genetic testing can provide information about a person’s genes and chromosomes. Available types of testing include:


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Newborn screening is used just after birth to identify genetic disorders that can be treated early in life. Millions of babies are tested each year in the United States. All states currently test infants for phenylketonuria (a genetic disorder that causes mental retardation if left untreated) and congenital hypothyroidism (a disorder of the thyroid gland). Most states also test for other genetic disorders.

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Diagnostic testing is used to identify or rule out a specific genetic or chromosomal condition. In many cases, genetic testing is used to confirm a diagnosis when a particular condition is suspected based on physical signs and symptoms. Diagnostic testing can be performed before birth or at any time during a person’s life, but is not available for all genes or all genetic conditions. The results of a diagnostic test can influence a person’s choices about health care and the management of the disorder.

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Carrier testing is used to identify people who carry one copy of a gene mutation that, when present in two copies, causes a genetic disorder. This type of testing is offered to individuals who have a family history of a genetic disorder and to people in certain ethnic groups with an increased risk of specific genetic conditions. If both parents are tested, the test can provide information about a couple’s risk of having a child with a genetic condition.

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Prenatal testing is used to detect changes in a fetus’s genes or chromosomes before birth. This type of testing is offered during pregnancy if there is an increased risk that the baby will have a genetic or chromosomal disorder. In some cases, prenatal testing can lessen a couple’s uncertainty or help them make decisions about a pregnancy. It cannot identify all possible inherited disorders and birth defects, however.

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Preimplantation testing, also called preimplantation genetic diagnosis (PGD), is a specialized technique that can reduce the risk of having a child with a particular genetic or chromosomal disorder. It is used to detect genetic changes in embryos that were created using assisted reproductive techniques such as in-vitro fertilization. In-vitro fertilization involves removing egg cells from a woman’s ovaries and fertilizing them with sperm cells outside the body. To perform preimplantation testing, a small number of cells are taken from these embryos and tested for certain genetic changes. Only embryos without these changes are implanted in the uterus to initiate a pregnancy.

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Predictive and presymptomatic types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a genetic disorder, but who have no features of the disorder themselves at the time of testing. Predictive testing can identify mutations that increase a person’s risk of developing disorders with a genetic basis, such as certain types of cancer. Presymptomatic testing can determine whether a person will develop a genetic disorder, such as hemochromatosis (an iron overload disorder), before any signs or symptoms appear. The results of predictive and presymptomatic testing can provide information about a person’s risk of developing a specific disorder and help with making decisions about medical care.

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Forensic testing uses DNA sequences to identify an individual for legal purposes. Unlike the tests described above, forensic testing is not used to detect gene mutations associated with disease. This type of testing can identify crime or catastrophe victims, rule out or implicate a crime suspect, or establish biological relationships between people (for example, paternity).

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How Is Genetic Testing Done? Once a person decides to proceed with genetic testing, a medical geneticist, primary care doctor, specialist, or nurse practitioner can order the test. Genetic testing is often done as part of a genetic consultation. Genetic tests are performed on a sample of blood, hair, skin, amniotic fluid (the fluid that surrounds a fetus during pregnancy), or other tissue. For example, a procedure called a buccal smear uses a small brush or cotton swab to collect a sample of cells from the inside surface of the cheek. The sample is sent to a laboratory where technicians look for specific changes in chromosomes, DNA, or proteins, depending on the suspected disorder. The laboratory reports the test results in writing to a person’s doctor or genetic counselor. Newborn screening tests are done on a small blood sample, which is taken by pricking the baby’s heel. Unlike other types of genetic testing, a parent will usually only receive the result if it is positive. If the test result is positive, additional testing is needed to determine whether the baby has a genetic disorder. Before a person has a genetic test, it is important that he or she understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission is called informed consent. What Is Direct-to-Consumer Genetic Testing? Traditionally, genetic tests have been available only through healthcare providers such as physicians, nurse practitioners, and genetic counselors. Healthcare providers order the appropriate test from a laboratory, collect and send the samples, and interpret the test results. Direct-to-consumer genetic testing refers to genetic tests that are marketed directly to consumers via television, print advertisements, or the Internet. This form of testing, which is also known as at-home genetic testing, provides access to a person’s genetic information without necessarily involving a doctor or insurance company in the process. If a consumer chooses to purchase a genetic test directly, the test kit is mailed to the consumer instead of being ordered through a doctor’s office. The test typically involves collecting a DNA sample at home, often by swabbing the inside of the cheek, and mailing the sample back to the laboratory. In some cases, the person must visit a health clinic to have blood drawn. Consumers are notified of their results by mail or over the telephone, or the results are posted online. In some cases, a genetic counselor or other healthcare provider is available to explain the results and answer questions. The price for this type of at-home genetic testing ranges from several hundred dollars to more than a thousand dollars. The growing market for direct-to-consumer genetic testing may promote awareness of genetic diseases, allow consumers to take a more proactive role in their health care, and offer a means for people to learn about their ancestral origins. At-home genetic tests, however, have significant risks and limitations. Consumers are vulnerable to being misled by the results of unproven or invalid tests. Without guidance from a healthcare provider, they may make important decisions about treatment or prevention based on inaccurate, incomplete, or misunderstood information about their health. Consumers may also experience an invasion of genetic privacy if testing companies use their genetic information in an unauthorized way.


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Genetic testing provides only one piece of information about a person’s health—other genetic and environmental factors, lifestyle choices, and family medical history also affect a person’s risk of developing many disorders. These factors are discussed during a consultation with a doctor or genetic counselor, but in many cases are not addressed by athome genetic tests. More research is needed to fully understand the benefits and limitations of direct-to-consumer genetic testing. What Do the Results of Genetic Tests Mean? The results of genetic tests are not always straightforward, which often makes them challenging to interpret and explain. Therefore, it is important for patients and their families to ask questions about the potential meaning of genetic test results both before and after the test is performed. When interpreting test results, healthcare professionals consider a person’s medical history, family history, and the type of genetic test that was done. A positive test result means that the laboratory found a change in a particular gene, chromosome, or protein of interest. Depending on the purpose of the test, this result may confirm a diagnosis, indicate that a person is a carrier of a particular genetic mutation, identify an increased risk of developing a disease (such as cancer) in the future, or suggest a need for further testing. Because family members have some genetic material in common, a positive test result may also have implications for certain blood relatives of the person undergoing testing. It is important to note that a positive result of a predictive or presymptomatic genetic test usually cannot establish the exact risk of developing a disorder. Also, health professionals typically cannot use a positive test result to predict the course or severity of a condition. A negative test result means that the laboratory did not find a change in the gene, chromosome, or protein under consideration. This result can indicate that a person is not affected by a particular disorder, is not a carrier of a specific genetic mutation, or does not have an increased risk of developing a certain disease. It is possible, however, that the test missed a disease-causing genetic alteration because many tests cannot detect all genetic changes that can cause a particular disorder. Further testing may be required to confirm a negative result. In some cases, a negative result might not give any useful information. This type of result is called uninformative, indeterminate, inconclusive, or ambiguous. Uninformative test results sometimes occur because everyone has common, natural variations in their DNA, called polymorphisms, that do not affect health. If a genetic test finds a change in DNA that has not been associated with a disorder in other people, it can be difficult to tell whether it is a natural polymorphism or a disease-causing mutation. An uninformative result cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder. In some cases, testing other affected and unaffected family members can help clarify this type of result. What Is the Cost of Genetic Testing, and How Long Does It Take to Get the Results? The cost of genetic testing can range from under $100 to more than $2,000, depending on the nature and complexity of the test. The cost increases if more than one test is necessary or if multiple family members must be tested to obtain a meaningful result. For newborn

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screening, costs vary by state. Some states cover part of the total cost, but most charge a fee of $15 to $60 per infant. From the date that a sample is taken, it may take a few weeks to several months to receive the test results. Results for prenatal testing are usually available more quickly because time is an important consideration in making decisions about a pregnancy. The doctor or genetic counselor who orders a particular test can provide specific information about the cost and time frame associated with that test. Will Health Insurance Cover the Costs of Genetic Testing? In many cases, health insurance plans will cover the costs of genetic testing when it is recommended by a person’s doctor. Health insurance providers have different policies about which tests are covered, however. A person interested in submitting the costs of testing may wish to contact his or her insurance company beforehand to ask about coverage. Some people may choose not to use their insurance to pay for testing because the results of a genetic test can affect a person’s health insurance coverage. Instead, they may opt to pay out-of-pocket for the test. People considering genetic testing may want to find out more about their state’s privacy protection laws before they ask their insurance company to cover the costs. What Are the Benefits of Genetic Testing? Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible. What Are the Risks and Limitations of Genetic Testing? The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a procedure that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus. Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern.


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Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed. A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision. What Is Genetic Discrimination? Genetic discrimination occurs when people are treated differently by their employer or insurance company because they have a gene mutation that causes or increases the risk of an inherited disorder. People who undergo genetic testing may be at risk for genetic discrimination. The results of a genetic test are normally included in a person’s medical records. When a person applies for life, disability, or health insurance, the insurance company may ask to look at these records before making a decision about coverage. An employer may also have the right to look at an employee’s medical records. As a result, genetic test results could affect a person’s insurance coverage or employment. People making decisions about genetic testing should be aware that when test results are placed in their medical records, the results might not be kept private. Fear of discrimination is a common concern among people considering genetic testing. Several laws at the federal and state levels help protect people against genetic discrimination; however, genetic testing is a fast-growing field and these laws don’t cover every situation. How Does Genetic Testing in a Research Setting Differ from Clinical Genetic Testing? The main differences between clinical genetic testing and research testing are the purpose of the test and who receives the results. The goals of research testing include finding unknown genes, learning how genes work, and advancing our understanding of genetic conditions. The results of testing done as part of a research study are usually not available to patients or their healthcare providers. Clinical testing, on the other hand, is done to find out about an inherited disorder in an individual patient or family. People receive the results of a clinical test and can use them to help them make decisions about medical care or reproductive issues. It is important for people considering genetic testing to know whether the test is available on a clinical or research basis. Clinical and research testing both involve a process of informed consent in which patients learn about the testing procedure, the risks and benefits of the test, and the potential consequences of testing.

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Gene Therapy This section presents information on experimental techniques, safety, ethics, and availability of gene therapy. What Is Gene Therapy? Gene therapy is an experimental technique that uses genes to treat or prevent disease. In the future, this technique may allow doctors to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Researchers are testing several approaches to gene therapy, including: •

Replacing a mutated gene that causes disease with a healthy copy of the gene.

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Inactivating, or “knocking out,” a mutated gene that is functioning improperly.

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Introducing a new gene into the body to help fight a disease.

Although gene therapy is a promising treatment option for a number of diseases (including inherited disorders, some types of cancer, and certain viral infections), the technique remains risky and is still under study to make sure that it will be safe and effective. Gene therapy is currently only being tested for the treatment of diseases that have no other cures. How Does Gene Therapy Work? Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. If a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein. A gene that is inserted directly into a cell usually does not function. Instead, a carrier called a vector is genetically engineered to deliver the gene. Certain viruses are often used as vectors because they can deliver the new gene by infecting the cell. The viruses are modified so they can’t cause disease when used in people. Some types of virus, such as retroviruses, integrate their genetic material (including the new gene) into a chromosome in the human cell. Other viruses, such as adenoviruses, introduce their DNA into the nucleus of the cell, but the DNA is not integrated into a chromosome. The vector can be injected or given intravenously (by IV) directly into a specific tissue in the body, where it is taken up by individual cells. Alternately, a sample of the patient’s cells can be removed and exposed to the vector in a laboratory setting. The cells containing the vector are then returned to the patient. If the treatment is successful, the new gene delivered by the vector will make a functioning protein. Researchers must overcome many technical challenges before gene therapy will be a practical approach to treating disease. For example, scientists must find better ways to deliver genes and target them to particular cells. They must also ensure that new genes are precisely controlled by the body.


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A new gene is injected into an adenovirus vector, which is used to introduce the modified DNA into a human cell. If the treatment is successful, the new gene will make a functional protein.

Is Gene Therapy Safe? Gene therapy is under study to determine whether it could be used to treat disease. Current research is evaluating the safety of gene therapy; future studies will test whether it is an effective treatment option. Several studies have already shown that this approach can have very serious health risks, such as toxicity, inflammation, and cancer. Because the techniques are relatively new, some of the risks may be unpredictable; however, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible. Comprehensive federal laws, regulations, and guidelines help protect people who participate in research studies (called clinical trials). The U.S. Food and Drug Administration (FDA) regulates all gene therapy products in the United States and oversees research in this area. Researchers who wish to test an approach in a clinical trial must first obtain permission from the FDA. The FDA has the authority to reject or suspend clinical trials that are suspected of being unsafe for participants. The National Institutes of Health (NIH) also plays an important role in ensuring the safety of gene therapy research. NIH provides guidelines for investigators and institutions (such as universities and hospitals) to follow when conducting clinical trials with gene therapy. These guidelines state that clinical trials at institutions receiving NIH funding for this type of research must be registered with the NIH Office of Biotechnology Activities. The protocol, or plan, for each clinical trial is then reviewed by the NIH Recombinant DNA Advisory Committee (RAC) to determine whether it raises medical, ethical, or safety issues that warrant further discussion at one of the RAC’s public meetings.

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An Institutional Review Board (IRB) and an Institutional Biosafety Committee (IBC) must approve each gene therapy clinical trial before it can be carried out. An IRB is a committee of scientific and medical advisors and consumers that reviews all research within an institution. An IBC is a group that reviews and approves an institution’s potentially hazardous research studies. Multiple levels of evaluation and oversight ensure that safety concerns are a top priority in the planning and carrying out of gene therapy research. What Are the Ethical Issues surrounding Gene Therapy? Because gene therapy involves making changes to the body’s set of basic instructions, it raises many unique ethical concerns. The ethical questions surrounding gene therapy include: •

How can “good” and “bad” uses of gene therapy be distinguished?

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Who decides which traits are normal and which constitute a disability or disorder?

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Will the high costs of gene therapy make it available only to the wealthy?

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Could the widespread use of gene therapy make society less accepting of people who are different?

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Should people be allowed to use gene therapy to enhance basic human traits such as height, intelligence, or athletic ability?

Current gene therapy research has focused on treating individuals by targeting the therapy to body cells such as bone marrow or blood cells. This type of gene therapy cannot be passed on to a person’s children. Gene therapy could be targeted to egg and sperm cells (germ cells), however, which would allow the inserted gene to be passed on to future generations. This approach is known as germline gene therapy. The idea of germline gene therapy is controversial. While it could spare future generations in a family from having a particular genetic disorder, it might affect the development of a fetus in unexpected ways or have long-term side effects that are not yet known. Because people who would be affected by germline gene therapy are not yet born, they can’t choose whether to have the treatment. Because of these ethical concerns, the U.S. Government does not allow federal funds to be used for research on germline gene therapy in people. Is Gene Therapy Available to Treat My Disorder? Gene therapy is currently available only in a research setting. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy products for sale in the United States. Hundreds of research studies (clinical trials) are under way to test gene therapy as a treatment for genetic conditions, cancer, and HIV/AIDS. If you are interested in participating in a clinical trial, talk with your doctor or a genetics professional about how to participate. You can also search for clinical trials online. ClinicalTrials.gov, a service of the National Institutes of Health, provides easy access to information on clinical trials. You can search for specific trials or browse by condition or trial sponsor. You may wish to refer to a list of gene therapy trials that are accepting (or will accept) patients.


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The Human Genome Project and Genomic Research This section presents information on the goals, accomplishments, and next steps in understanding the human genome. What Is a Genome? A genome is an organism’s complete set of DNA, including all of its genes. Each genome contains all of the information needed to build and maintain that organism. In humans, a copy of the entire genome—more than 3 billion DNA base pairs—is contained in all cells that have a nucleus. What Was the Human Genome Project and Why Has It Been Important? The Human Genome Project was an international research effort to determine the sequence of the human genome and identify the genes that it contains. The Project was coordinated by the National Institutes of Health and the U.S. Department of Energy. Additional contributors included universities across the United States and international partners in the United Kingdom, France, Germany, Japan, and China. The Human Genome Project formally began in 1990 and was completed in 2003, 2 years ahead of its original schedule. The work of the Human Genome Project has allowed researchers to begin to understand the blueprint for building a person. As researchers learn more about the functions of genes and proteins, this knowledge will have a major impact in the fields of medicine, biotechnology, and the life sciences. What Were the Goals of the Human Genome Project? The main goals of the Human Genome Project were to provide a complete and accurate sequence of the 3 billion DNA base pairs that make up the human genome and to find all of the estimated 20,000 to 25,000 human genes. The Project also aimed to sequence the genomes of several other organisms that are important to medical research, such as the mouse and the fruit fly. In addition to sequencing DNA, the Human Genome Project sought to develop new tools to obtain and analyze the data and to make this information widely available. Also, because advances in genetics have consequences for individuals and society, the Human Genome Project committed to exploring the consequences of genomic research through its Ethical, Legal, and Social Implications (ELSI) program. What Did the Human Genome Project Accomplish? In April 2003, researchers announced that the Human Genome Project had completed a high-quality sequence of essentially the entire human genome. This sequence closed the gaps from a working draft of the genome, which was published in 2001. It also identified the locations of many human genes and provided information about their structure and

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organization. The Project made the sequence of the human genome and tools to analyze the data freely available via the Internet. In addition to the human genome, the Human Genome Project sequenced the genomes of several other organisms, including brewers’ yeast, the roundworm, and the fruit fly. In 2002, researchers announced that they had also completed a working draft of the mouse genome. By studying the similarities and differences between human genes and those of other organisms, researchers can discover the functions of particular genes and identify which genes are critical for life. The Project’s Ethical, Legal, and Social Implications (ELSI) program became the world’s largest bioethics program and a model for other ELSI programs worldwide. What Were Some of the Ethical, Legal, and Social Implications Addressed by the Human Genome Project? The Ethical, Legal, and Social Implications (ELSI) program was founded in 1990 as an integral part of the Human Genome Project. The mission of the ELSI program was to identify and address issues raised by genomic research that would affect individuals, families, and society. A percentage of the Human Genome Project budget at the National Institutes of Health and the U.S. Department of Energy was devoted to ELSI research. The ELSI program focused on the possible consequences of genomic research in four main areas: •

Privacy and fairness in the use of genetic information, including the potential for genetic discrimination in employment and insurance.

•

The integration of new genetic technologies, such as genetic testing, into the practice of clinical medicine.

•

Ethical issues surrounding the design and conduct of genetic research with people, including the process of informed consent.

•

The education of healthcare professionals, policy makers, students, and the public about genetics and the complex issues that result from genomic research. What Are the Next Steps in Genomic Research?

Discovering the sequence of the human genome was only the first step in understanding how the instructions coded in DNA lead to a functioning human being. The next stage of genomic research will begin to derive meaningful knowledge from the DNA sequence. Research studies that build on the work of the Human Genome Project are under way worldwide. The objectives of continued genomic research include the following: •

Determine the function of genes and the elements that regulate genes throughout the genome.

•

Find variations in the DNA sequence among people and determine their significance. These variations may one day provide information about a person’s disease risk and response to certain medications.


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•

Discover the 3-dimensional structures of proteins and identify their functions.

•

Explore how DNA and proteins interact with one another and with the environment to create complex living systems.

•

Develop and apply genome-based strategies for the early detection, diagnosis, and treatment of disease.

•

Sequence the genomes of other organisms, such as the rat, cow, and chimpanzee, in order to compare similar genes between species.

•

Develop new technologies to study genes and DNA on a large scale and store genomic data efficiently.

•

Continue to explore the ethical, legal, and social issues raised by genomic research. What Is Pharmacogenomics?

Pharmacogenomics is the study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup. Many drugs that are currently available are “one size fits all,” but they don’t work the same way for everyone. It can be difficult to predict who will benefit from a medication, who will not respond at all, and who will experience negative side effects (called adverse drug reactions). Adverse drug reactions are a significant cause of hospitalizations and deaths in the United States. With the knowledge gained from the Human Genome Project, researchers are learning how inherited differences in genes affect the body’s response to medications. These genetic differences will be used to predict whether a medication will be effective for a particular person and to help prevent adverse drug reactions. The field of pharmacogenomics is still in its infancy. Its use is currently quite limited, but new approaches are under study in clinical trials. In the future, pharmacogenomics will allow the development of tailored drugs to treat a wide range of health problems, including cardiovascular disease, Alzheimer disease, cancer, HIV/AIDS, and asthma.

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APPENDIX B. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute43: •

National Institutes of Health (NIH); guidelines consolidated across agencies available at http://health.nih.gov/

•

National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/Publications/FactSheets.htm

•

National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

•

National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancertopics/pdq

•

National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/health/

•

National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

•

National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

•

National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/HealthInformation/Publications/

•

National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/Publications/

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These publications are typically written by one or more of the various NIH Institutes.

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•

National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

•

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

•

National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidcr.nih.gov/HealthInformation/

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/healthinformation/index.cfm

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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

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National Institute of Biomedical Imaging and Bioengineering; general information at http://www.nibib.nih.gov/HealthEdu

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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

•

Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.44 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic

44

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html).

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citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine45: •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

•

HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/index.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

•

Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

•

Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

•

Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

•

Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

•

MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

•

Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

•

Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

45

See http://www.nlm.nih.gov/databases/index.html.

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The NLM Gateway46 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.47 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type nonsyndromic deafness (or synonyms) into the search box and click Search. The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 294 0 12 0 0 306

HSTAT48 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.49 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.50 Simply search by nonsyndromic deafness (or synonyms) at the following Web site: http://text.nlm.nih.gov. Coffee Break: Tutorials for Biologists51 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. 46

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

47

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 48 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 49 50

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration’s Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force’s Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations. 51 Adapted from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

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Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.52 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.53 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

MD Consult: Access to electronic clinical resources, see http://www.mdconsult.com/.

•

Medical Matrix: Lists over 6000 medical Web sites and links to over 1.5 million documents with clinical content, see http://www.medmatrix.org/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

52

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 53 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process.

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APPENDIX C. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called Fact Sheets or Guidelines. They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on nonsyndromic deafness can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources This section directs you to sources which either publish fact sheets or can help you find additional guidelines on topics related to nonsyndromic deafness. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are health topic pages which list links to available materials relevant to nonsyndromic deafness. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for nonsyndromic deafness:

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Brain Cancer http://www.nlm.nih.gov/medlineplus/braincancer.html Childhood Brain Tumors http://www.nlm.nih.gov/medlineplus/childhoodbraintumors.html Ear Infections http://www.nlm.nih.gov/medlineplus/earinfections.html Hearing Disorders and Deafness http://www.nlm.nih.gov/medlineplus/hearingdisordersanddeafness.html Hearing Problems in Children http://www.nlm.nih.gov/medlineplus/hearingproblemsinchildren.html Neurofibromatosis http://www.nlm.nih.gov/medlineplus/neurofibromatosis.html Neurologic Diseases http://www.nlm.nih.gov/medlineplus/neurologicdiseases.html Schizophrenia http://www.nlm.nih.gov/medlineplus/schizophrenia.html Speech and Communication Disorders http://www.nlm.nih.gov/medlineplus/speechandcommunicationdisorders.html Taste and Smell Disorders http://www.nlm.nih.gov/medlineplus/tasteandsmelldisorders.html Usher Syndrome http://www.nlm.nih.gov/medlineplus/ushersyndrome.html Vision Impairment and Blindness http://www.nlm.nih.gov/medlineplus/visionimpairmentandblindness.html You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click Search. This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search. Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

MedlinePlus: Hearing Disorders and Deafness Source: www.nlm.nih.gov http://www.nlm.nih.gov/medlineplus/hearingdisordersanddeafness.html

Patient Resources

•

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Winter 1999 [NIDCD Inside] Source: www.nidcd.nih.gov http://www.nidcd.nih.gov/health/inside/wtr99/defaultpage.asp The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to nonsyndromic deafness. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://health.nih.gov/index.asp. Under Search Health Topics, type nonsyndromic deafness (or synonyms) into the search box, and click Search. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

Family Village: http://www.familyvillage.wisc.edu/specific.htm

•

Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

•

Med Help International: http://www.medhelp.org/HealthTopics/A.html

•

Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

•

Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

•

WebMD®Health: http://www.webmd.com/diseases_and_conditions/default.htm

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to nonsyndromic deafness. By consulting all of associations listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with nonsyndromic deafness. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about nonsyndromic deafness. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797.

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Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://sis.nlm.nih.gov/dirline.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. Simply type in nonsyndromic deafness (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://healthhotlines.nlm.nih.gov/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type nonsyndromic deafness (or a synonym) into the search box, and click Submit Query.

Resources for Patients and Families The following are organizations that provide support and advocacy for patient with genetic conditions and their families54: •

Genetic Alliance: http://geneticalliance.org

•

Genetic and Rare Diseases Information Center: http://rarediseases.info.nih.gov/html/resources/info_cntr.html

•

Madisons Foundation: http://www.madisonsfoundation.org/

•

March of Dimes: http://www.marchofdimes.com

•

National Organization for Rare Disorders (NORD): http://www.rarediseases.org/ For More Information on Genetics

The following publications offer detailed information for patients about the science of genetics: •

54

What Is a Genome?: http://www.ncbi.nlm.nih.gov/About/primer/genetics_genome.html

Adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/ghr/resource/patients.

Patient Resources

•

A Science Called Genetics: http://publications.nigms.nih.gov/genetics/science.html

•

Genetic Mapping: http://www.genome.gov/10000715

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/archive//20040831/nichsr/ta101/ta10108.html

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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NONSYNDROMIC DEAFNESS DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Acidosis: A pathologic condition resulting from accumulation of acid or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, and characterized by an increase in hydrogen ion concentration. [EU] Acoustic: Having to do with sound or hearing. [NIH] Actin: Essential component of the cell skeleton. [NIH] Adaptability: Ability to develop some form of tolerance to conditions extremely different from those under which a living organism evolved. [NIH] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenosine Diphosphate: Adenosine 5'-(trihydrogen diphosphate). An adenine nucleotide containing two phosphate groups esterified to the sugar moiety at the 5'-position. [NIH] Adenosine Triphosphate: Adenosine 5'-(tetrahydrogen triphosphate). An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. [NIH] Adenovirus: A group of viruses that cause respiratory tract and eye infections. Adenoviruses used in gene therapy are altered to carry a specific tumor-fighting gene. [NIH] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association

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constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alkaline: Having the reactions of an alkali. [EU] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Ameliorated: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aneuploidy: The chromosomal constitution of cells which deviate from the normal by the addition or subtraction of chromosomes or chromosome pairs. In a normally diploid cell the loss of a chromosome pair is termed nullisomy (symbol: 2N-2), the loss of a single chromosome is monosomy (symbol: 2N-1), the addition of a chromosome pair is tetrasomy (symbol: 2N+2), the addition of a single chromosome is trisomy (symbol: 2N+1). [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibody: A type of protein made by certain white blood cells in response to a foreign

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substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Anti-infective: An agent that so acts. [EU] Anuria: Inability to form or excrete urine. [NIH] Anus: The opening of the rectum to the outside of the body. [NIH] Aplasia: Lack of development of an organ or tissue, or of the cellular products from an organ or tissue. [EU] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Aqueous: Having to do with water. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Artery: Vessel-carrying blood from the heart to various parts of the body. [NIH] Articular: Of or pertaining to a joint. [EU] Assay: Determination of the amount of a particular constituent of a mixture, or of the biological or pharmacological potency of a drug. [EU] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Audiology: The study of hearing and hearing impairment. [NIH] Auditory: Pertaining to the sense of hearing. [EU]

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Auditory nerve: The eight cranial nerve; also called vestibulocochlear nerve or acoustic nerve. [NIH] Axons: Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Infections: Infections by bacteria, general or unspecified. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Base Sequence: The sequence of purines and pyrimidines in nucleic acids and polynucleotides. It is also called nucleotide or nucleoside sequence. [NIH] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Benign: Not cancerous; does not invade nearby tissue or spread to other parts of the body. [NIH]

Benign tumor: A noncancerous growth that does not invade nearby tissue or spread to other parts of the body. [NIH] Bewilderment: Impairment or loss of will power. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Bladder: The organ that stores urine. [NIH] Blastocyst: The mammalian embryo in the post-morula stage in which a fluid-filled cavity,

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enclosed primarily by trophoblast, contains an inner cell mass which becomes the embryonic disc. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Fluids: Liquid components of living organisms. [NIH] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Carbohydrates: The largest class of organic compounds, including starches, glycogens, cellulose, gums, and simple sugars. Carbohydrates are composed of carbon, hydrogen, and oxygen in a ratio of Cn(H2O)n. [NIH] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenic: Producing carcinoma. [EU] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which

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can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carotene: The general name for a group of pigments found in green, yellow, and leafy vegetables, and yellow fruits. The pigments are fat-soluble, unsaturated aliphatic hydrocarbons functioning as provitamins and are converted to vitamin A through enzymatic processes in the intestinal wall. [NIH] Cations: Postively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. [NIH] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Cycle: The complex series of phenomena, occurring between the end of one cell division and the end of the next, by which cellular material is divided between daughter cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Movement: The movement of cells from one location to another. [NIH] Cell Polarity: Orientation of intracellular structures especially with respect to the apical and basolateral domains of the plasma membrane. Polarized cells must direct proteins from the Golgi apparatus to the appropriate domain since tight junctions prevent proteins from diffusing between the two domains. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cellular Structures: Components of a cell. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Centromere: The clear constricted portion of the chromosome at which the chromatids are joined and by which the chromosome is attached to the spindle during cell division. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU] Cerebral Cortex: The thin layer of gray matter on the surface of the cerebral hemisphere that develops from the telencephalon and folds into gyri. It reaches its highest development in man and is responsible for intellectual faculties and higher mental functions. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Character: In current usage, approximately equivalent to personality. The sum of the relatively fixed personality traits and habitual modes of response of an individual. [NIH] Chin: The anatomical frontal portion of the mandible, also known as the mentum, that contains the line of fusion of the two separate halves of the mandible (symphysis menti). This line of fusion divides inferiorly to enclose a triangular area called the mental

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protuberance. On each side, inferior to the second premolar tooth, is the mental foramen for the passage of blood vessels and a nerve. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Chorioretinitis: Inflammation of the choroid in which the sensory retina becomes edematous and opaque. The inflammatory cells and exudate may burst through the sensory retina to cloud the vitreous body. [NIH] Choroid: The thin, highly vascular membrane covering most of the posterior of the eye between the retina and sclera. [NIH] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chromosome Fragility: Susceptibility of chromosomes to breakage and translocation or other aberrations. Chromosome fragile sites are regions that show up in karyotypes as a gap (uncondensed stretch) on the chromatid arm. They are associated with chromosome break sites and other aberrations. A fragile site on the X chromosome is associated with fragile X syndrome. Fragile sites are designated by the letters "FRA" followed by the designation for the specific chromosome and a letter which refers to the different fragile sites on a chromosome (e.g. FRAXA). [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Cirrhosis: A type of chronic, progressive liver disease. [NIH] CIS: Cancer Information Service. The CIS is the National Cancer Institute's link to the public, interpreting and explaining research findings in a clear and understandable manner, and providing personalized responses to specific questions about cancer. Access the CIS by calling 1-800-4-CANCER, or by using the Web site at http://cis.nci.nih.gov. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Cleft Palate: Congenital fissure of the soft and/or hard palate, due to faulty fusion. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Cochlea: The part of the internal ear that is concerned with hearing. It forms the anterior part of the labyrinth, is conical, and is placed almost horizontally anterior to the vestibule. [NIH]

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Cochlear: Of or pertaining to the cochlea. [EU] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Colon: The long, coiled, tubelike organ that removes water from digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus. [NIH] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT)

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scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Concentric: Having a common center of curvature or symmetry. [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Cones: One type of specialized light-sensitive cells (photoreceptors) in the retina that provide sharp central vision and color vision. [NIH] Confusion: A mental state characterized by bewilderment, emotional disturbance, lack of clear thinking, and perceptual disorientation. [NIH] Congenita: Displacement, subluxation, or malposition of the crystalline lens. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue Cells: A group of cells that includes fibroblasts, cartilage cells, adipocytes, smooth muscle cells, and bone cells. [NIH] Connexins: A group of homologous proteins which form the intermembrane channels of gap junctions. The connexins are the products of an identified gene family which has both highly conserved and highly divergent regions. The variety contributes to the wide range of functional properties of gap junctions. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constitutional: 1. Affecting the whole constitution of the body; not local. 2. Pertaining to the constitution. [EU] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Corneum: The superficial layer of the epidermis containing keratinized cells. [NIH] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Corpus: The body of the uterus. [NIH] Cranial: Pertaining to the cranium, or to the anterior (in animals) or superior (in humans) end of the body. [EU] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU]

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Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cystine: A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. [NIH]

Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytogenetics: A branch of genetics which deals with the cytological and molecular behavior of genes and chromosomes during cell division. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytosine: A pyrimidine base that is a fundamental unit of nucleic acids. [NIH] Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Death Certificates: Official records of individual deaths including the cause of death certified by a physician, and any other required identifying information. [NIH] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Dementia: An acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behavior, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. [NIH] Deoxyribonucleic: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleic acid: A polymer of subunits called deoxyribonucleotides which is the primary genetic material of a cell, the material equivalent to genetic information. [NIH] Deoxyribonucleotides: A purine or pyrimidine base bonded to a deoxyribose containing a bond to a phosphate group. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH]

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Diploid: Having two sets of chromosomes. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Discrete: Made up of separate parts or characterized by lesions which do not become blended; not running together; separate. [NIH] Discrimination: The act of qualitative and/or quantitative differentiation between two or more stimuli. [NIH] Disorientation: The loss of proper bearings, or a state of mental confusion as to time, place, or identity. [EU] Diuretic: A drug that increases the production of urine. [NIH] Dizziness: An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. [NIH] Duodenum: The first part of the small intestine. [NIH] Dynein: A transport protein that normally binds proteins to the microtubule. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eardrum: A thin, tense membrane forming the greater part of the outer wall of the tympanic cavity and separating it from the external auditory meatus; it constitutes the boundary between the external and middle ear. [NIH] Ectoderm: The outer of the three germ layers of the embryo. [NIH] Ectodermal Dysplasia: A group of hereditary disorders involving tissues and structures derived from the embryonic ectoderm. They are characterized by the presence of abnormalities at birth and involvement of both the epidermis and skin appendages. They are generally nonprogressive and diffuse. Various forms exist, including anhidrotic and hidrotic dysplasias, focal dermal hypoplasia, and aplasia cutis congenita. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Effector cell: A cell that performs a specific function in response to a stimulus; usually used to describe cells in the immune system. [NIH] Elastic: Susceptible of resisting and recovering from stretching, compression or distortion applied by a force. [EU] Elastin: The protein that gives flexibility to tissues. [NIH] Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrocoagulation: Electrosurgical procedures used to treat hemorrhage (e.g., bleeding ulcers) and to ablate tumors, mucosal lesions, and refractory arrhythmias. [NIH] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid

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morphological changes and the differentiation of basic structures. [NIH] Emulsion: A preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Pharmaceutical emulsions for which official standards have been promulgated include cod liver oil emulsion, cod liver oil emulsion with malt, liquid petrolatum emulsion, and phenolphthalein in liquid petrolatum emulsion. [EU] Encephalopathy: A disorder of the brain that can be caused by disease, injury, drugs, or chemicals. [NIH] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endolymphatic Duct: Duct connecting the endolymphatic sac with the membranous labyrinth. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Epidermis: Nonvascular layer of the skin. It is made up, from within outward, of five layers: 1) basal layer (stratum basale epidermidis); 2) spinous layer (stratum spinosum epidermidis); 3) granular layer (stratum granulosum epidermidis); 4) clear layer (stratum lucidum epidermidis); and 5) horny layer (stratum corneum epidermidis). [NIH] Epidermodysplasia Verruciformis: An autosomal recessive trait with impaired cellmediated immunity. About 15 human papillomaviruses are implicated in associated infection, four of which lead to skin neoplasms. The disease begins in childhood with red papules and later spreads over the body as gray or yellow scales. [NIH] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which covers the inner or outer surfaces of the body. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Eukaryotic Cells: Cells of the higher organisms, containing a true nucleus bounded by a nuclear membrane. [NIH] Excitatory: When cortical neurons are excited, their output increases and each new input they receive while they are still excited raises their output markedly. [NIH]

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Excrete: To get rid of waste from the body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Eye Color: Color of the iris. [NIH] Eye Infections: Infection, moderate to severe, caused by bacteria, fungi, or viruses, which occurs either on the external surface of the eye or intraocularly with probable inflammation, visual impairment, or blindness. [NIH] Facial: Of or pertaining to the face. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fat: Total lipids including phospholipids. [NIH] Fathers: Male parents, human or animal. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fissure: Any cleft or groove, normal or otherwise; especially a deep fold in the cerebral cortex which involves the entire thickness of the brain wall. [EU] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU]

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Fold: A plication or doubling of various parts of the body. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Fovea: The central part of the macula that provides the sharpest vision. [NIH] Frameshift: A type of mutation which causes out-of-phase transcription of the base sequence; such mutations arise from the addition or delection of nucleotide(s) in numbers other than 3 or multiples of 3. [NIH] Frameshift Mutation: A type of mutation in which a number of nucleotides not divisible by three is deleted from or inserted into a coding sequence, thereby causing an alteration in the reading frame of the entire sequence downstream of the mutation. These mutations may be induced by certain types of mutagens or may occur spontaneously. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gap Junctions: Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Gene Products, rev: Trans-acting nuclear proteins whose functional expression are required for HIV viral replication. Specifically, the rev gene products are required for processing and translation of the HIV gag and env mRNAs, and thus rev regulates the expression of the viral structural proteins. rev can also regulate viral regulatory proteins. A cis-acting antirepression sequence (CAR) in env, also known as the rev-responsive element (RRE), is responsive to the rev gene product. rev is short for regulator of virion. [NIH] Gene Therapy: The introduction of new genes into cells for the purpose of treating disease by restoring or adding gene expression. Techniques include insertion of retroviral vectors, transfection, homologous recombination, and injection of new genes into the nuclei of single cell embryos. The entire gene therapy process may consist of multiple steps. The new genes may be introduced into proliferating cells in vivo (e.g., bone marrow) or in vitro (e.g., fibroblast cultures) and the modified cells transferred to the site where the gene expression is required. Gene therapy may be particularly useful for treating enzyme deficiency diseases, hemoglobinopathies, and leukemias and may also prove useful in restoring drug sensitivity, particularly for leukemia. [NIH] Genes, env: DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH]

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Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genomics: The systematic study of the complete DNA sequences (genome) of organisms. [NIH]

Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Germline mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; germline mutations are passed on from parents to offspring. Also called hereditary mutation. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glutamate: Excitatory neurotransmitter of the brain. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Granule: A small pill made from sucrose. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Guanine: One of the four DNA bases. [NIH] Hair Cells: Mechanoreceptors located in the organ of Corti that are sensitive to auditory stimuli and in the vestibular apparatus that are sensitive to movement of the head. In each case the accessory sensory structures are arranged so that appropriate stimuli cause movement of the hair-like projections (stereocilia and kinocilia) which relay the information centrally in the nervous system. [NIH] Hair Color: Color of hair or fur. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Helix-loop-helix: Regulatory protein of cell cycle. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have

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failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinopathies: A group of inherited disorders characterized by structural alterations within the hemoglobin molecule. [NIH] Hemophilia: Refers to a group of hereditary disorders in which affected individuals fail to make enough of certain proteins needed to form blood clots. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Hereditary mutation: A gene change in the body's reproductive cells (egg or sperm) that becomes incorporated into the DNA of every cell in the body of offspring; hereditary mutations are passed on from parents to offspring. Also called germline mutation. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heterogeneity: The property of one or more samples or populations which implies that they are not identical in respect of some or all of their parameters, e. g. heterogeneity of variance. [NIH]

Histones: Small chromosomal proteins (approx 12-20 kD) possessing an open, unfolded structure and attached to the DNA in cell nuclei by ionic linkages. Classification into the various types (designated histone I, histone II, etc.) is based on the relative amounts of arginine and lysine in each. [NIH] Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Horny layer: The superficial layer of the epidermis containing keratinized cells. [NIH] Human papillomavirus: HPV. A virus that causes abnormal tissue growth (warts) and is often associated with some types of cancer. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH]

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Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrophic cardiomyopathy: Heart muscle disease that leads to thickening of the heart walls, interfering with the heart's ability to fill with and pump blood. [NIH] Hypoplasia: Incomplete development or underdevelopment of an organ or tissue. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunity: Nonsusceptibility to the invasive or pathogenic microorganisms or to the toxic effect of antigenic substances. [NIH]

effects

of

foreign

Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] Implantation: The insertion or grafting into the body of biological, living, inert, or radioactive material. [EU] In situ: In the natural or normal place; confined to the site of origin without invasion of neighbouring tissues. [EU] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Infancy: The period of complete dependency prior to the acquisition of competence in walking, talking, and self-feeding. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Informed Consent: Voluntary authorization, given to the physician by the patient, with full comprehension of the risks involved, for diagnostic or investigative procedures and medical and surgical treatment. [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inner ear: The labyrinth, comprising the vestibule, cochlea, and semicircular canals. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own

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psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intracellular Membranes: Membranes of subcellular structures. [NIH] Iodine: A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. [NIH] Ion Channels: Gated, ion-selective glycoproteins that traverse membranes. The stimulus for channel gating can be a membrane potential, drug, transmitter, cytoplasmic messenger, or a mechanical deformation. Ion channels which are integral parts of ionotropic neurotransmitter receptors are not included. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Iris: The most anterior portion of the uveal layer, separating the anterior chamber from the posterior. It consists of two layers - the stroma and the pigmented epithelium. Color of the iris depends on the amount of melanin in the stroma on reflection from the pigmented epithelium. [NIH] Karyotype: The characteristic chromosome complement of an individual, race, or species as defined by their number, size, shape, etc. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kidney Failure, Acute: A clinical syndrome characterized by a sudden decrease in glomerular filtration rate, often to values of less than 1 to 2 ml per minute. It is usually associated with oliguria (urine volumes of less than 400 ml per day) and is always associated with biochemical consequences of the reduction in glomerular filtration rate such as a rise in blood urea nitrogen (BUN) and serum creatinine concentrations. [NIH] Kidney Failure, Chronic: An irreversible and usually progressive reduction in renal function in which both kidneys have been damaged by a variety of diseases to the extent that they are unable to adequately remove the metabolic products from the blood and regulate the body's electrolyte composition and acid-base balance. Chronic kidney failure requires hemodialysis or surgery, usually kidney transplantation. [NIH] Labyrinth: The internal ear; the essential part of the organ of hearing. It consists of an osseous and a membranous portion. [NIH]

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Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Lectin: A complex molecule that has both protein and sugars. Lectins are able to bind to the outside of a cell and cause biochemical changes in it. Lectins are made by both animals and plants. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipid: Fat. [NIH] Lipoma: A benign tumor composed of fat cells. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphatic system: The tissues and organs that produce, store, and carry white blood cells that fight infection and other diseases. This system includes the bone marrow, spleen, thymus, lymph nodes and a network of thin tubes that carry lymph and white blood cells. These tubes branch, like blood vessels, into all the tissues of the body. [NIH] Lymphocytes: White blood cells formed in the body's lymphoid tissue. The nucleus is round or ovoid with coarse, irregularly clumped chromatin while the cytoplasm is typically pale blue with azurophilic (if any) granules. Most lymphocytes can be classified as either T or B (with subpopulations of each); those with characteristics of neither major class are called

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null cells. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Lysine: An essential amino acid. It is often added to animal feed. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Mammography: Radiographic examination of the breast. [NIH] Meatus: A canal running from the internal auditory foramen through the petrous portion of the temporal bone. It gives passage to the facial and auditory nerves together with the auditory branch of the basilar artery and the internal auditory veins. [NIH] Medical Records: Recording of pertinent information concerning patient's illness or illnesses. [NIH] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Meiosis: A special method of cell division, occurring in maturation of the germ cells, by means of which each daughter nucleus receives half the number of chromosomes characteristic of the somatic cells of the species. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanophores: Chromatophores (large pigment cells of fish, amphibia, reptiles and many invertebrates) which contain melanin. Short term color changes are brought about by an active redistribution of the melanophores pigment containing organelles (melanosomes). Mammals do not have melanophores; however they have retained smaller pigment cells known as melanocytes. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]

Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Glycoproteins: Glycoproteins found on the membrane or surface of cells. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH]

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Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH] Mental: Pertaining to the mind; psychic. 2. (L. mentum chin) pertaining to the chin. [EU] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Retardation: Refers to sub-average general intellectual functioning which originated during the developmental period and is associated with impairment in adaptive behavior. [NIH]

Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Microvilli: Minute projections of cell membranes which greatly increase the surface area of the cell. [NIH] Migration: The systematic movement of genes between populations of the same species, geographic race, or variety. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monosomy: The condition in which one chromosome of a pair is missing. In a normally diploid cell it is represented symbolically as 2N-1. [NIH] Morphological: Relating to the configuration or the structure of live organs. [NIH] Mosaicism: The occurrence in an individual of two or more cell populations of different chromosomal constitutions, derived from a single zygote, as opposed to chimerism in which the different cell populations are derived from more than one zygote. [NIH] Motility: The ability to move spontaneously. [EU] Motor nerve: An efferent nerve conveying an impulse that excites muscular contraction. [NIH]

Muscle Contraction: A process leading to shortening and/or development of tension in muscle tissue. Muscle contraction occurs by a sliding filament mechanism whereby actin filaments slide inward among the myosin filaments. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic

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unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Myoclonus: Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous systems diseases (e.g., epilepsy, myoclonic). Nocturnal myoclonus may represent a normal physiologic event or occur as the principal feature of the nocturnal myoclonus syndrome. (From Adams et al., Principles of Neurology, 6th ed, pp102-3). [NIH] Myopathy: Any disease of a muscle. [EU] Myosin: Chief protein in muscle and the main constituent of the thick filaments of muscle fibers. In conjunction with actin, it is responsible for the contraction and relaxation of muscles. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Neoplasms: New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuroendocrine: Having to do with the interactions between the nervous system and the endocrine system. Describes certain cells that release hormones into the blood in response to stimulation of the nervous system. [NIH] Neurologic: Having to do with nerves or the nervous system. [NIH] Neurology: A medical specialty concerned with the study of the structures, functions, and diseases of the nervous system. [NIH] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuroretinitis: Inflammation of the optic nerve head and adjacent retina. [NIH] Neurotransmitter: Any of a group of substances that are released on excitation from the axon terminal of a presynaptic neuron of the central or peripheral nervous system and travel across the synaptic cleft to either excite or inhibit the target cell. Among the many

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substances that have the properties of a neurotransmitter are acetylcholine, norepinephrine, epinephrine, dopamine, glycine, y-aminobutyrate, glutamic acid, substance P, enkephalins, endorphins, and serotonin. [EU] Night Blindness: Anomaly of vision in which there is a pronounced inadequacy or complete absence of dark-adaptation. [NIH] Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Envelope: The membrane system of the cell nucleus that surrounds the nucleoplasm. It consists of two concentric membranes separated by the perinuclear space. The structures of the envelope where it opens to the cytoplasm are called the nuclear pores (nuclear pore). [NIH] Nuclear Pore: An opening through the nuclear envelope formed by the nuclear pore complex which transports nuclear proteins or RNA into or out of the cell nucleus and which, under some conditions, acts as an ion channel. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nurse Practitioners: Nurses who are specially trained to assume an expanded role in providing medical care under the supervision of a physician. [NIH] Ocular: 1. Of, pertaining to, or affecting the eye. 2. Eyepiece. [EU] Oculomotor: Cranial nerve III. It originate from the lower ventral surface of the midbrain and is classified as a motor nerve. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Operon: The genetic unit consisting of a feedback system under the control of an operator gene, in which a structural gene transcribes its message in the form of mRNA upon blockade of a repressor produced by a regulator gene. Included here is the attenuator site of bacterial operons where transcription termination is regulated. [NIH] Ophthalmology: A surgical specialty concerned with the structure and function of the eye and the medical and surgical treatment of its defects and diseases. [NIH] Opsin: A protein formed, together with retinene, by the chemical breakdown of metarhodopsin. [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

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Optic Nerve: The 2nd cranial nerve. The optic nerve conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other important targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. [NIH] Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH] Osteoarthritis: A progressive, degenerative joint disease, the most common form of arthritis, especially in older persons. The disease is thought to result not from the aging process but from biochemical changes and biomechanical stresses affecting articular cartilage. In the foreign literature it is often called osteoarthrosis deformans. [NIH] Osteogenic sarcoma: A malignant tumor of the bone. Also called osteosarcoma. [NIH] Osteosarcoma: A cancer of the bone that affects primarily children and adolescents. Also called osteogenic sarcoma. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds. [NIH] Palate: The structure that forms the roof of the mouth. It consists of the anterior hard palate and the posterior soft palate. [NIH] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Particle: A tiny mass of material. [EU] Patch: A piece of material used to cover or protect a wound, an injured part, etc.: a patch over the eye. [NIH] Paternity: Establishing the father relationship of a man and a child. [NIH] Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] PDQ: Physician Data Query. PDQ is an online database developed and maintained by the National Cancer Institute. Designed to make the most current, credible, and accurate cancer information available to health professionals and the public, PDQ contains peer-reviewed summaries on cancer treatment, screening, prevention, genetics, and supportive care; a registry of cancer clinical trials from around the world; and directories of physicians, professionals who provide genetics services, and organizations that provide cancer care. Most of this information is available on the CancerNet Web site, and more specific information about PDQ can be found at http://cancernet.nci.nih.gov/pdq.html. [NIH]

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Pedigree: A record of one's ancestors, offspring, siblings, and their offspring that may be used to determine the pattern of certain genes or disease inheritance within a family. [NIH] Pelvis: The lower part of the abdomen, located between the hip bones. [NIH] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Perception: The ability quickly and accurately to recognize similarities and differences among presented objects, whether these be pairs of words, pairs of number series, or multiple sets of these or other symbols such as geometric figures. [NIH] Perilymph: The fluid contained within the space separating the membranous from the osseous labyrinth of the ear. [NIH] Phagocytosis: The engulfing of microorganisms, other cells, and foreign particles by phagocytic cells. [NIH] Phallic: Pertaining to the phallus, or penis. [EU] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Photocoagulation: Using a special strong beam of light (laser) to seal off bleeding blood vessels such as in the eye. The laser can also burn away blood vessels that should not have grown in the eye. This is the main treatment for diabetic retinopathy. [NIH] Photoreceptor: Receptor capable of being activated by light stimuli, as a rod or cone cell of the eye. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plastids: Self-replicating cytoplasmic organelles of plant and algal cells that contain

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pigments and may synthesize and accumulate various substances. Plastids are used in phylogenetic studies. [NIH] Pneumonia: Inflammation of the lungs. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potassium Channels: Cell membrane glycoproteins selective for potassium ions. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Progeny: The offspring produced in any generation. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proinsulin: The substance made first in the pancreas that is then made into insulin. When insulin is purified from the pancreas of pork or beef, all the proinsulin is not fully removed. When some people use these insulins, the proinsulin can cause the body to react with a rash, to resist the insulin, or even to make dents or lumps in the skin at the place where the insulin is injected. The purified insulins have less proinsulin and other impurities than the other types of insulins. [NIH] Projection: A defense mechanism, operating unconsciously, whereby that which is emotionally unacceptable in the self is rejected and attributed (projected) to others. [NIH]

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Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Folding: A rapid biochemical reaction involved in the formation of proteins. It begins even before a protein has been completely synthesized and proceeds through discrete intermediates (primary, secondary, and tertiary structures) before the final structure (quaternary structure) is developed. [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Protein Subunits: Single chains of amino acids that are the units of a multimeric protein. They can be identical or non-identical subunits. [NIH] Protein Transport: The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Psychiatric: Pertaining to or within the purview of psychiatry. [EU] Psychiatry: The medical science that deals with the origin, diagnosis, prevention, and treatment of mental disorders. [NIH] Psychic: Pertaining to the psyche or to the mind; mental. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary Edema: An accumulation of an excessive amount of watery fluid in the lungs, may be caused by acute exposure to dangerous concentrations of irritant gasses. [NIH] Pulposus: Prolapse of the nucleus pulposus into the body of the vertebra; necrobacillosis of rabbits. [NIH]

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Purified Insulins: Insulins with much less of the impure proinsulin. It is thought that the use of purified insulins may help avoid or reduce some of the problems of people with diabetes such as allergic reactions. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (cytosine, thymine, and uracil) and form the basic structure of the barbiturates. [NIH] Quaternary: 1. Fourth in order. 2. Containing four elements or groups. [EU] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Recombination: The formation of new combinations of genes as a result of segregation in crosses between genetically different parents; also the rearrangement of linked genes due to crossing-over. [NIH] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Repressor: Any of the specific allosteric protein molecules, products of regulator genes, which bind to the operator of operons and prevent RNA polymerase from proceeding into the operon to transcribe messenger RNA. [NIH] Reproductive cells: Egg and sperm cells. Each mature reproductive cell carries a single set of 23 chromosomes. [NIH]

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Respiratory distress syndrome: A lung disease that occurs primarily in premature infants; the newborn must struggle for each breath and blueing of its skin reflects the baby's inability to get enough oxygen. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinal Ganglion Cells: Cells of the innermost nuclear layer of the retina, the ganglion cell layer, which project axons through the optic nerve to the brain. They are quite variable in size and in the shapes of their dendritic arbors, which are generally confined to the inner plexiform layer. [NIH] Retinal pigment epithelium: The pigment cell layer that nourishes the retinal cells; located just outside the retina and attached to the choroid. [NIH] Retinitis: Inflammation of the retina. It is rarely limited to the retina, but is commonly associated with diseases of the choroid (chorioretinitis) and of the optic nerve (neuroretinitis). The disease may be confined to one eye, but since it is generally dependent on a constitutional factor, it is almost always bilateral. It may be acute in course, but as a rule it lasts many weeks or even several months. [NIH] Retinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field. [NIH] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinol: Vitamin A. It is essential for proper vision and healthy skin and mucous membranes. Retinol is being studied for cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Retroviral vector: RNA from a virus that is used to insert genetic material into cells. [NIH] Rhodopsin: A photoreceptor protein found in retinal rods. It is a complex formed by the binding of retinal, the oxidized form of retinol, to the protein opsin and undergoes a series of complex reactions in response to visible light resulting in the transmission of nerve impulses to the brain. [NIH] Ribonucleic acid: RNA. One of the two nucleic acids found in all cells. The other is deoxyribonucleic acid (DNA). Ribonucleic acid transfers genetic information from DNA to proteins produced by the cell. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Rod: A reception for vision, located in the retina. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH]

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Satellite: Applied to a vein which closely accompanies an artery for some distance; in cytogenetics, a chromosomal agent separated by a secondary constriction from the main body of the chromosome. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Scatter: The extent to which relative success and failure are divergently manifested in qualitatively different tests. [NIH] Schizophrenia: A mental disorder characterized by a special type of disintegration of the personality. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Sella: A deep depression in the shape of a Turkish saddle in the upper surface of the body of the sphenoid bone in the deepest part of which is lodged the hypophysis cerebri. [NIH] Sella Turcica: A bony prominence situated on the upper surface of the body of the sphenoid bone. It houses the pituitary gland. [NIH] Semicircular canal: Three long canals of the bony labyrinth of the ear, forming loops and opening into the vestibule by five openings. [NIH] Sequela: Any lesion or affection following or caused by an attack of disease. [EU] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signs and Symptoms: Clinical manifestations that can be either objective when observed by a physician, or subjective when perceived by the patient. [NIH]

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Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Social Work: The use of community resources, individual case work, or group work to promote the adaptive capacities of individuals in relation to their social and economic environments. It includes social service agencies. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Soma: The body as distinct from the mind; all the body tissue except the germ cells; all the axial body. [NIH] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatic cells: All the body cells except the reproductive (germ) cells. [NIH] Somatic mutations: Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other diseases. [NIH] Sound wave: An alteration of properties of an elastic medium, such as pressure, particle displacement, or density, that propagates through the medium, or a superposition of such alterations. [NIH] Spatial disorientation: Loss of orientation in space where person does not know which way is up. [NIH] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH]

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Spinous: Like a spine or thorn in shape; having spines. [NIH] Spiral Lamina: The bony plate which extends outwards from the modiolus. It is part of the structure which divides trhe cochlea into sections. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stillbirth: The birth of a dead fetus or baby. [NIH] Stimulant: 1. Producing stimulation; especially producing stimulation by causing tension on muscle fibre through the nervous tissue. 2. An agent or remedy that produces stimulation. [EU]

Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Subspecies: A category intermediate in rank between species and variety, based on a smaller number of correlated characters than are used to differentiate species and generally conditioned by geographical and/or ecological occurrence. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Supportive care: Treatment given to prevent, control, or relieve complications and side effects and to improve the comfort and quality of life of people who have cancer. [NIH] Synapses: Specialized junctions at which a neuron communicates with a target cell. At classical synapses, a neuron's presynaptic terminal releases a chemical transmitter stored in synaptic vesicles which diffuses across a narrow synaptic cleft and activates receptors on the postsynaptic membrane of the target cell. The target may be a dendrite, cell body, or axon of another neuron, or a specialized region of a muscle or secretory cell. Neurons may also communicate through direct electrical connections which are sometimes called electrical synapses; these are not included here but rather in gap junctions. [NIH] Systemic: Affecting the entire body. [NIH] Tectorial Membrane: A gelatinous membrane, attached to the bony spiral lamina, which overlies the hair cells within the cochlea of the inner ear. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH]

Dictionary 191

Tetracycline: An antibiotic originally produced by Streptomyces viridifaciens, but used mostly in synthetic form. It is an inhibitor of aminoacyl-tRNA binding during protein synthesis. [NIH] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH]

192


Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Trinucleotide Repeat Expansion: DNA region comprised of a variable number of repetitive, contiguous trinucleotide sequences. The presence of these regions is associated with diseases such as Fragile X Syndrome and myotonic dystrophy. Many chromosome fragile sites (chromosome fragility) contain expanded trinucleotide repeats. [NIH] Trinucleotide Repeats: Microsatellite repeats consisting of three nucleotides dispersed in the euchromatic arms of chromosomes. [NIH] Trisomy: The possession of a third chromosome of any one type in an otherwise diploid cell. [NIH]

Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Ultraviolet radiation: Invisible rays that are part of the energy that comes from the sun. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Valine: A branched-chain essential amino acid that has stimulant activity. It promotes muscle growth and tissue repair. It is a precursor in the penicillin biosynthetic pathway. [NIH]

Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH]

Dictionary 193

Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Ventral: 1. Pertaining to the belly or to any venter. 2. Denoting a position more toward the belly surface than some other object of reference; same as anterior in human anatomy. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Vertebrae: A bony unit of the segmented spinal column. [NIH] Vesicular: 1. Composed of or relating to small, saclike bodies. 2. Pertaining to or made up of vesicles on the skin. [EU] Vestibular: Pertaining to or toward a vestibule. In dental anatomy, used to refer to the tooth surface directed toward the vestibule of the mouth. [EU] Vestibular Aqueduct: A small bony canal linking the vestibule of the inner ear to the posterior part of the internal surface of the petrous temporal bone. It surrounds the endolymphatic duct. [NIH] Vestibule: A small, oval, bony chamber of the labyrinth. The vestibule contains the utricle and saccule, organs which are part of the balancing apparatus of the ear. [NIH] Vestibulocochlear Nerve: The 8th cranial nerve. The vestibulocochlear nerve has a cochlear part (cochlear nerve) which is concerned with hearing and a vestibular part (vestibular nerve) which mediates the sense of balance and head position. The fibers of the cochlear nerve originate from neurons of the spiral ganglion and project to the cochlear nuclei (cochlear nucleus). The fibers of the vestibular nerve arise from neurons of Scarpa's ganglion and project to the vestibular nuclei. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Viscera: Any of the large interior organs in any one of the three great cavities of the body, especially in the abdomen. [NIH] Visual field: The entire area that can be seen when the eye is forward, including peripheral vision. [NIH] Vitreous: Glasslike or hyaline; often used alone to designate the vitreous body of the eye (corpus vitreum). [EU] Vitreous Body: The transparent, semigelatinous substance that fills the cavity behind the crystalline lens of the eye and in front of the retina. It is contained in a thin hyoid membrane and forms about four fifths of the optic globe. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Voltage-gated: It is opened by the altered charge distribution across the cell membrane.

194


[NIH]

White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Womb: A hollow, thick-walled, muscular organ in which the impregnated ovum is developed into a child. [NIH] Wound Healing: Restoration of integrity to traumatized tissue. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zona Pellucida: The transport non-cellular envelope surrounding the mammalian ovum. [NIH]

Zygote: The fertilized ovum. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

195

INDEX 3 3-dimensional, 15, 21, 66, 76, 116, 147, 159 A Abdomen, 159, 163, 170, 176, 177, 182, 183, 190, 193 Abdominal, 159, 182 Acidosis, 11, 159 Acoustic, 159, 162 Actin, 14, 15, 16, 32, 33, 46, 48, 49, 50, 71, 72, 73, 84, 102, 117, 159, 179, 180 Adaptability, 159, 164 Adenine, 110, 159, 186 Adenosine, 11, 12, 44, 78, 111, 159, 183 Adenosine Diphosphate, 12, 159 Adenosine Triphosphate, 11, 44, 78, 111, 159, 183 Adenovirus, 143, 159 Adverse Effect, 159, 188 Aerobic, 159, 179 Afferent, 31, 159 Affinity, 159, 189 Algorithms, 160, 162 Alkaline, 159, 160, 163 Alleles, 57, 65, 70, 86, 112, 129, 160, 177 Alpha-1, 125, 129, 160 Ameliorated, 88, 160 Amino Acid Sequence, 160, 171 Amnion, 160 Amniotic Fluid, 138, 140, 160 Anal, 160, 171 Anatomical, 160, 164, 175, 188 Anemia, 124, 125, 128, 129, 134, 160 Aneuploidy, 122, 123, 160 Animal model, 86, 160 Anions, 160, 176 Antibacterial, 160, 189 Antibiotic, 78, 160, 183, 189, 191 Antibody, 117, 160, 161, 166, 174, 175, 186 Anticoagulant, 161, 185 Antigen, 56, 159, 160, 161, 166, 174, 175 Anti-infective, 161, 176 Anuria, 161, 176 Anus, 160, 161, 166 Aplasia, 161, 169 Apoptosis, 111, 120, 161 Aqueous, 161, 162, 168, 170, 177 Arginine, 24, 161, 174 Arterial, 161, 175, 185 Arteries, 161, 163, 167

Arterioles, 161, 163 Artery, 161, 178, 188 Articular, 161, 182 Assay, 86, 161 Ataxia, 12, 161, 191 Atypical, 133, 161 Audiology, 7, 161 Auditory, 28, 30, 31, 41, 43, 47, 54, 55, 62, 67, 80, 82, 86, 161, 162, 169, 173, 178 Auditory nerve, 28, 30, 43, 62, 67, 80, 82, 162, 178 Axons, 162, 182, 187 B Bacteria, 109, 117, 121, 160, 161, 162, 171, 179, 189, 191, 192 Bacterial Infections, 79, 162 Basal Ganglia, 161, 162 Basal Ganglia Diseases, 161, 162 Base Sequence, 121, 162, 172 Basement Membrane, 162, 171 Benign, 162, 177, 180 Benign tumor, 162, 177 Bewilderment, 162, 167 Bilateral, 4, 162, 187 Bile, 162, 177 Biochemical, 90, 125, 160, 162, 176, 177, 182, 185 Biosynthesis, 162, 188 Biotechnology, 6, 116, 143, 145, 150, 162 Bladder, 162, 192 Blastocyst, 162, 167 Blood Coagulation, 163, 191 Blood Glucose, 76, 163, 174, 176 Blood pressure, 128, 163, 164, 175, 179, 189 Blood vessel, 132, 163, 164, 165, 177, 183, 189, 190, 191, 192 Body Fluids, 163, 189 Bone Marrow, 144, 163, 172, 177 Bone scan, 163, 188 Bowel, 160, 163, 176, 190 Buccal, 138, 140, 163 C Calcium, 53, 76, 80, 81, 163, 166 Calmodulin, 52, 163 Carbohydrates, 163, 164 Carbon Dioxide, 163, 171 Carcinogenic, 163, 175, 185 Cardiomyopathy, 163 Cardiovascular, 147, 163

196


Cardiovascular disease, 147, 163 Carotene, 164, 187 Cations, 164, 176 Cause of Death, 164, 168 Cell Cycle, 119, 120, 164, 173 Cell Death, 120, 161, 164, 180 Cell Division, 71, 89, 112, 119, 120, 132, 133, 162, 164, 168, 178, 179, 183 Cell membrane, 16, 55, 60, 73, 164, 172, 179, 184, 193 Cell Movement, 14, 32, 46, 48, 50, 71, 84, 164 Cell Polarity, 90, 164 Cell Respiration, 164, 179 Cellular Structures, 44, 78, 164 Central Nervous System, 58, 164, 172, 173, 180, 182 Centromere, 112, 115, 164 Cerebellar, 161, 164, 186 Cerebral, 161, 162, 164, 171 Cerebral Cortex, 161, 164, 171 Cerebrovascular, 162, 164, 191 Character, 164, 168 Chin, 164, 179 Cholesterol, 111, 162, 165, 167 Chorioretinitis, 165, 187 Choroid, 165, 187 Chromatin, 161, 165, 177 Chromosomal, 89, 120, 122, 123, 133, 134, 135, 137, 160, 165, 174, 179, 188 Chromosome, 91, 92, 93, 94, 97, 98, 99, 100, 104 Chromosome Fragility, 165, 192 Chronic, 79, 165, 175, 176 Cirrhosis, 165, 173 CIS, 165, 172, 187 Clamp, 86, 165 Cleft Palate, 26, 165 Clinical Medicine, 146, 165, 184 Clinical trial, 86, 143, 144, 147, 150, 165, 182, 185 Cloning, 87, 98, 162, 165 Coagulation, 20, 163, 165 Cochlea, 4, 21, 26, 27, 30, 35, 42, 52, 53, 60, 71, 86, 87, 88, 90, 105, 165, 166, 175, 190 Cochlear, 20, 67, 85, 86, 90, 98, 101, 166, 193 Codon, 26, 117, 166 Cofactor, 166, 185, 191 Collagen, 23, 24, 25, 26, 162, 166, 171, 185 Colon, 11, 126, 166, 177 Colonoscopy, 128, 166

Complement, 166, 172, 176 Computational Biology, 150, 166 Computed tomography, 166, 167, 188 Computerized axial tomography, 166, 167, 188 Concentric, 167, 181 Conception, 119, 167, 171, 189 Cones, 167, 187 Confusion, 126, 167, 169, 192 Congenita, 167, 169 Connective Tissue, 23, 24, 163, 166, 167, 171, 172 Connective Tissue Cells, 167 Connexins, 37, 40, 84, 86, 90, 167, 172 Consciousness, 167, 168 Constitutional, 167, 187 Constriction, 112, 115, 167, 188 Consultation, 134, 135, 138, 139, 167 Contraindications, ii, 167 Corneum, 167, 170 Coronary, 163, 167 Coronary heart disease, 163, 167 Corpus, 167, 193 Cranial, 162, 167, 181, 182, 193 Cyclic, 163, 167, 188 Cysteine, 22, 24, 65, 168 Cystine, 168 Cytochrome, 168, 182 Cytogenetics, 168, 188 Cytoplasm, 109, 110, 111, 117, 161, 164, 168, 173, 177, 181, 187 Cytosine, 110, 168, 186 Cytoskeleton, 14, 33, 71, 73, 89, 168 D De novo, 100, 120, 168 Death Certificates, 128, 168 Degenerative, 87, 168, 182 Deletion, 9, 28, 39, 40, 42, 59, 91, 122, 161, 168 Dementia, 12, 123, 168 Deoxyribonucleic, 110, 168, 187 Deoxyribonucleic acid, 110, 168, 187 Deoxyribonucleotides, 168 Diabetes Mellitus, 77, 101, 168, 173, 174 Digestion, 69, 162, 163, 168, 176, 177, 190, 192 Dilated cardiomyopathy, 35, 168 Diploid, 160, 169, 179, 183, 192 Direct, iii, 30, 82, 83, 138, 139, 140, 164, 165, 169, 186, 190 Discrete, 169, 185 Discrimination, 140, 141, 146, 169

Index 197

Disorientation, 167, 169 Diuretic, 99, 169 Dizziness, 58, 169 Duodenum, 162, 169, 190 Dynein, 89, 169 Dysplasia, 24, 26, 169 Dystrophy, 94, 169 E Eardrum, 4, 169 Ectoderm, 169 Ectodermal Dysplasia, 40, 169 Effector, 89, 166, 169 Effector cell, 169 Elastic, 169, 189 Elastin, 166, 169 Elective, 169 Electrocoagulation, 165, 169 Electrolyte, 169, 176, 184, 189 Electrons, 162, 169, 176, 186 Embryo, 119, 120, 121, 129, 160, 162, 169 Emulsion, 170, 171 Encephalopathy, 11, 170 Endocrine System, 170, 180 Endocytosis, 50, 170 Endolymphatic Duct, 170, 193 Environmental Health, 149, 150, 170 Enzymatic, 163, 164, 166, 170, 187 Enzyme, 11, 12, 80, 81, 111, 117, 169, 170, 172, 184, 185, 191, 193, 194 Epidermis, 36, 38, 82, 167, 169, 170, 174 Epidermodysplasia Verruciformis, 67, 170 Epigastric, 170, 182 Epithelial, 69, 70, 84, 170 Epithelial Cells, 84, 170 Epithelium, 51, 52, 57, 162, 170, 176 Erythrocytes, 160, 163, 170 Esophagus, 170, 190 Ethnic Groups, 134, 137, 170 Eukaryotic Cells, 90, 170, 182 Excitatory, 170, 173 Excrete, 161, 171, 176 Exocrine, 171, 182 Exon, 26, 28, 171 Extracellular, 21, 167, 170, 171, 185, 189 Extracellular Matrix, 21, 167, 171 Extracellular Space, 171 Eye Color, 121, 171 Eye Infections, 159, 171 F Facial, 25, 171, 178 Family Planning, 150, 171 Fat, 163, 164, 167, 171, 177, 189

Fathers, 6, 129, 171 Fatigue, 171, 173 Fetus, 137, 138, 140, 144, 171, 184, 190, 192 Fibroblasts, 89, 167, 171 Fibrosis, 121, 124, 128, 129, 171, 188 Fissure, 165, 171 Fixation, 9, 59, 171 Fold, 76, 171, 172 Forearm, 163, 172 Fovea, 171, 172 Frameshift, 30, 122, 172 Frameshift Mutation, 30, 122, 172 G Ganglia, 162, 172, 180 Gap Junctions, 35, 36, 38, 39, 82, 86, 90, 167, 172, 190 Gastrin, 172, 174 Gene, 91, 92, 94, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106 Gene Expression, 117, 118, 172 Gene Products, rev, 172 Gene Therapy, 142, 143, 144, 159, 172 Genes, 96, 101, 104, 105 Genes, env, 128, 172 Genetic Engineering, 162, 165, 172 Genetic testing, 10, 131, 135, 136, 137, 138, 139, 140, 141, 146, 172 Genomics, 10, 22, 28, 37, 53, 67, 75, 147, 173 Genotype, 26, 42, 61, 62, 65, 88, 173, 183 Germ Cells, 120, 144, 173, 178, 189 Germline mutation, 120, 173, 174 Gland, 173, 182, 183, 188, 191 Glucose, 76, 163, 168, 173, 174, 176 Glucose Intolerance, 168, 173 Glutamate, 173 Glutamic Acid, 24, 25, 173, 181, 185 Glycine, 24, 25, 26, 173, 181, 188 Governing Board, 173, 184 Granule, 173, 187 Granulocytes, 173, 177, 194 Guanine, 72, 110, 173, 186 H Hair Cells, 14, 15, 29, 42, 43, 47, 57, 62, 75, 80, 86, 88, 173, 190 Hair Color, 121, 173 Heart attack, 164, 173 Heart failure, 14, 173 Helix-loop-helix, 89, 173 Hemochromatosis, 137, 173 Hemodialysis, 173, 176 Hemoglobin, 111, 160, 170, 174

198


Hemoglobinopathies, 172, 174 Hemophilia, 129, 174 Hemorrhage, 169, 174, 190 Hereditary, 7, 10, 11, 15, 26, 30, 53, 105, 106, 109, 110, 120, 129, 135, 169, 173, 174, 187 Hereditary mutation, 120, 173, 174 Heredity, 112, 172, 173, 174 Heterogeneity, 17, 18, 52, 57, 61, 75, 95, 103, 159, 174 Histones, 112, 165, 174 Homeostasis, 90, 174 Homologous, 35, 160, 167, 172, 174 Hormone, 76, 117, 172, 174, 176, 178, 188, 191 Horny layer, 170, 174 Human papillomavirus, 170, 174 Hydrogen, 159, 162, 163, 174, 179 Hydrolysis, 174, 184, 185 Hydroxylysine, 166, 175 Hydroxyproline, 166, 175 Hypertension, 164, 175 Hypertrophic cardiomyopathy, 50, 175 Hypoplasia, 169, 175 Hypothalamus, 175, 183 I Immune response, 161, 175, 190, 193 Immune system, 11, 169, 175, 178, 192, 194 Immunity, 170, 175 Impairment, 7, 9, 10, 14, 15, 24, 25, 28, 35, 40, 46, 61, 65, 68, 77, 80, 87, 91, 92, 94, 95, 97, 99, 101, 103, 104, 105, 106, 154, 161, 162, 171, 175, 179 Implantation, 167, 175 In situ, 90, 175 In vitro, 20, 70, 86, 89, 90, 172, 175 In vivo, 90, 172, 175 Infancy, 147, 175 Infection, 170, 171, 175, 177, 180, 183, 194 Inflammation, 69, 143, 165, 171, 175, 180, 184, 187 Informed Consent, 138, 141, 146, 175 Initiation, 175, 191 Insight, 86, 87, 175 Insulin, 76, 176, 184 Insulin-dependent diabetes mellitus, 176 Intestinal, 19, 84, 164, 176 Intestine, 84, 163, 176, 177 Intracellular, 164, 175, 176, 178, 184, 188 Intracellular Membranes, 176, 178 Iodine, 60, 176 Ion Channels, 176

Ions, 19, 35, 36, 38, 39, 41, 60, 76, 80, 82, 86, 162, 163, 169, 174, 176, 184 Iris, 171, 176 K Karyotype, 114, 176 Kidney Failure, 12, 123, 176 Kidney Failure, Acute, 176 Kidney Failure, Chronic, 176 L Labyrinth, 42, 165, 170, 175, 176, 183, 188, 193 Large Intestine, 176, 177, 186, 189 Lectin, 177, 178 Lens, 37, 167, 177, 193 Lesion, 177, 188 Lethal, 83, 177 Leucocyte, 160, 177 Leukemia, 11, 172, 177 Linkage, 75, 87, 88, 177 Linkage Disequilibrium, 75, 177 Lipid, 176, 177 Lipoma, 42, 44, 102, 177 Liver, 11, 19, 80, 118, 159, 162, 165, 170, 173, 177, 188 Liver scan, 177, 188 Localization, 85, 87, 105, 177 Localized, 88, 171, 175, 177, 183 Loop, 177 Lymph, 86, 177 Lymphatic, 175, 177 Lymphatic system, 177 Lymphocytes, 161, 177, 178, 194 Lymphoid, 177, 178 Lymphoma, 11, 178 Lysine, 174, 175, 178 M Macrophage, 120, 178 Magnetic Resonance Imaging, 178, 188 Malignancy, 14, 178 Mammography, 128, 178 Meatus, 169, 178 Medical Records, 128, 141, 178 MEDLINE, 150, 178 Meiosis, 119, 178 Melanocytes, 178 Melanoma, 178, 192 Melanophores, 178 Melanosomes, 51, 178 Membrane Glycoproteins, 178 Membrane Proteins, 90, 178 Memory, 168, 178 Meninges, 164, 179

Index 199

Mental, iv, 85, 133, 135, 137, 149, 151, 164, 167, 168, 169, 171, 178, 179, 185, 188, 192 Mental Health, iv, 85, 149, 151, 179, 185 Mental Retardation, 133, 135, 137, 179 Microbe, 179, 191 Microbiology, 161, 179 Microorganism, 166, 179, 193 Microvilli, 32, 33, 84, 179 Migration, 89, 179 Miscarriage, 140, 179 Mitochondria, 10, 11, 12, 44, 78, 110, 111, 123, 129, 130, 179, 182 Mitosis, 119, 161, 179 Molecular, 95, 98 Molecule, 12, 23, 30, 44, 69, 78, 110, 111, 112, 117, 161, 162, 166, 169, 174, 177, 179, 186, 192 Monitor, 179, 181 Monosomy, 123, 160, 179 Morphological, 170, 178, 179 Mosaicism, 120, 179 Motility, 71, 179 Motor nerve, 179, 181 Muscle Contraction, 14, 179 Muscle Fibers, 179, 180 Mutagens, 172, 180 Myoclonus, 46, 180 Myopathy, 46, 180 Myosin, 18, 46, 47, 48, 49, 50, 51, 52, 53, 57, 74, 84, 85, 94, 104, 106, 179, 180 Myotonic Dystrophy, 132, 180, 192 N NCI, 1, 148, 165, 180, 182 Necrosis, 161, 180 Neoplasms, 170, 180, 191 Nervous System, 132, 159, 164, 173, 180, 190 Neural, 159, 180 Neuroendocrine, 48, 180 Neurologic, 99, 154, 180 Neurology, 14, 180 Neurons, 170, 172, 180, 190, 193 Neuropathy, 11, 12, 31, 54, 55, 129, 180 Neuroretinitis, 180, 187 Neurotransmitter, 159, 173, 176, 180, 188, 190 Night Blindness, 181, 187 Nitrogen, 171, 176, 181, 192 Nuclear, 97 Nuclear Envelope, 110, 181 Nuclear Pore, 181

Nuclei, 169, 172, 174, 178, 179, 181, 182, 193 Nucleic acid, 162, 168, 180, 181, 186, 187 Nurse Practitioners, 138, 181 O Ocular, 26, 181 Oculomotor, 22, 181 Oliguria, 176, 181 Operon, 181, 186 Ophthalmology, 171, 181 Opsin, 181, 187 Optic Chiasm, 175, 181, 182 Optic Nerve, 11, 180, 181, 182, 187 Organelles, 109, 110, 168, 178, 182, 183 Osteoarthritis, 26, 182 Osteogenic sarcoma, 182 Osteosarcoma, 89, 182 Ovaries, 137, 182 Ovum, 182, 194 Oxidative Phosphorylation, 11, 12, 44, 78, 111, 182 P Palate, 165, 182 Pancreas, 76, 159, 173, 176, 182, 184 Pancreatic, 71, 182 Pancreatic cancer, 71, 182 Particle, 182, 189, 191 Patch, 86, 182 Paternity, 137, 182 Pathologic, 22, 159, 161, 167, 182 Pathologic Processes, 161, 182 PDQ, 148, 182 Pedigree, 42, 93, 97, 104, 183 Pelvis, 159, 182, 183, 192 Penicillin, 183, 192 Peptide, 183, 184, 185 Perception, 67, 183 Perilymph, 22, 86, 183 Phagocytosis, 52, 183 Phallic, 171, 183 Pharmacologic, 183, 191 Phenotype, 17, 26, 42, 53, 59, 61, 62, 65, 88, 95, 183 Phosphorus, 163, 183 Phosphorylation, 11, 44, 78, 111, 183 Photocoagulation, 165, 183 Photoreceptor, 16, 29, 55, 57, 73, 183, 187 Physical Examination, 135, 183 Physiologic, 162, 180, 183, 186 Pigment, 51, 178, 183, 187 Pituitary Gland, 46, 183, 188 Plants, 163, 173, 177, 183, 191

200


Plasma, 80, 81, 110, 164, 173, 174, 176, 183 Plastids, 182, 183 Pneumonia, 167, 184 Polymerase, 184, 186 Polymorphism, 139, 184 Polypeptide, 160, 166, 184, 194 Polysaccharide, 161, 184 Posterior, 160, 161, 165, 176, 182, 184, 193 Post-translational, 22, 184 Potassium, 35, 36, 38, 39, 40, 41, 42, 86, 184 Potassium Channels, 41, 184 Practice Guidelines, 151, 184 Precursor, 76, 169, 170, 184, 192 Prenatal, 137, 140, 169, 184 Prevalence, 106, 125, 184 Progeny, 87, 184 Progression, 67, 160, 184 Progressive, 16, 22, 27, 46, 65, 92, 94, 98, 123, 165, 168, 176, 180, 182, 184, 187 Proinsulin, 76, 184, 186 Projection, 182, 184, 186 Proline, 166, 175, 185 Promoter, 89, 185 Prone, 11, 123, 132, 185 Protease, 68, 70, 71, 185 Protein Folding, 76, 185 Protein Subunits, 41, 185 Protein Transport, 60, 185 Proteolytic, 70, 71, 160, 166, 185 Protocol, 143, 185 Psychiatric, 77, 101, 185 Psychiatry, 171, 185 Psychic, 179, 185 Public Health, 88, 151, 185 Public Policy, 150, 185 Pulmonary, 163, 176, 185 Pulmonary Artery, 163, 185 Pulmonary Edema, 176, 185 Pulposus, 23, 185 Purified Insulins, 184, 186 Purines, 162, 186, 188 Pyrimidines, 162, 186, 188 Q Quaternary, 185, 186 R Race, 176, 179, 186 Radiation, 159, 186, 188, 192, 194 Radiation therapy, 159, 186 Radioactive, 163, 174, 175, 177, 181, 186, 188 Receptor, 32, 126, 161, 183, 186 Recombinant, 143, 186, 192

Recombination, 172, 186 Rectum, 161, 166, 177, 186 Red Nucleus, 161, 186 Refer, 1, 115, 119, 121, 126, 144, 163, 166, 169, 171, 177, 186, 193 Refraction, 186, 189 Regeneration, 88, 186 Repressor, 89, 181, 186 Reproductive cells, 122, 133, 134, 173, 174, 186 Respiratory distress syndrome, 99, 187 Retina, 16, 28, 30, 49, 50, 52, 55, 73, 165, 167, 177, 180, 181, 182, 187, 193 Retinal, 50, 52, 55, 181, 182, 187 Retinal Ganglion Cells, 182, 187 Retinal pigment epithelium, 50, 187 Retinitis, 12, 57, 107, 187 Retinitis Pigmentosa, 12, 57, 107, 187 Retinoblastoma, 125, 187 Retinol, 187 Retroviral vector, 172, 187 Rhodopsin, 181, 187 Ribonucleic acid, 117, 187 Ribose, 159, 187 Ribosome, 117, 187, 192 Rod, 165, 183, 187 S Salivary, 182, 187 Satellite, 71, 188 Scans, 88, 188 Scatter, 188, 192 Schizophrenia, 130, 154, 188 Sclerosis, 126, 188 Screening, 7, 9, 61, 83, 88, 128, 137, 138, 140, 165, 182, 188 Second Messenger Systems, 188 Secretion, 22, 176, 188, 192 Sella, 183, 188 Sella Turcica, 183, 188 Semicircular canal, 175, 188 Sequela, 99, 188 Sequencing, 88, 145, 188 Serine, 44, 68, 69, 70, 71, 188 Shock, 180, 188 Side effect, 144, 147, 159, 188, 190, 191 Skeletal, 24, 165, 189 Skeleton, 159, 189 Skull, 189, 190 Small intestine, 169, 174, 176, 189 Social Work, 134, 189 Sodium, 69, 70, 189 Soft tissue, 163, 189

Index 201

Soma, 189 Somatic, 11, 120, 123, 134, 178, 179, 189 Somatic cells, 120, 123, 134, 178, 179, 189 Somatic mutations, 11, 123, 189 Sound wave, 16, 19, 27, 28, 30, 32, 35, 38, 39, 41, 43, 46, 48, 50, 55, 62, 64, 65, 66, 67, 71, 73, 80, 81, 82, 189 Spatial disorientation, 169, 189 Specialist, 138, 155, 189 Species, 147, 176, 178, 179, 186, 189, 190, 192, 193, 194 Spectrum, 61, 77, 96, 101, 189 Sperm, 119, 120, 122, 123, 132, 133, 134, 137, 144, 165, 173, 174, 186, 189 Spinal cord, 30, 80, 164, 165, 179, 180, 189 Spinous, 170, 190 Spiral Lamina, 190 Sporadic, 187, 190 Stabilization, 89, 190 Staging, 188, 190 Steel, 30, 48, 52, 165, 190 Stillbirth, 135, 190 Stimulant, 190, 192 Stomach, 11, 159, 170, 172, 174, 189, 190 Stool, 166, 177, 190 Strand, 110, 184, 190 Stroke, 11, 128, 149, 164, 190 Subspecies, 189, 190 Supportive care, 182, 190 Synapses, 190 Systemic, 163, 175, 186, 190 T Tectorial Membrane, 63, 64, 190 Temporal, 90, 178, 190, 193 Terminator, 166, 190 Tetracycline, 89, 191 Thalamic, 161, 191 Thalamic Diseases, 161, 191 Threonine, 188, 191 Thrombin, 185, 191 Thrombomodulin, 185, 191 Thrombosis, 185, 190, 191 Thyroid, 60, 137, 176, 191 Thyroid Gland, 137, 191 Thyroid Hormones, 60, 191 Tissue, 98 Toxic, iv, 109, 175, 180, 191 Toxicity, 79, 143, 191 Toxicology, 150, 191 Toxins, 161, 175, 191 Trachea, 191 Traction, 165, 191

Transcription Factors, 58, 89, 118, 191 Transduction, 57, 191 Transfection, 162, 172, 191 Translation, 117, 118, 172, 192 Translational, 192 Translocation, 165, 185, 192 Trinucleotide Repeat Expansion, 132, 192 Trinucleotide Repeats, 192 Trisomy, 123, 160, 192 Tryptophan, 166, 192 Tuberculosis, 79, 192 U Ultraviolet radiation, 120, 192 Uremia, 176, 192 Urethra, 192 Urine, 60, 161, 162, 169, 176, 181, 192 Uterus, 137, 167, 182, 192 V Vaccine, 185, 192 Vacuoles, 170, 182, 192 Valine, 81, 192 Vascular, 165, 175, 191, 192 Vector, 142, 143, 191, 192 Vein, 181, 188, 193 Venous, 185, 193 Ventral, 175, 181, 193 Venules, 163, 193 Vertebrae, 23, 189, 193 Vesicular, 185, 193 Vestibular, 21, 22, 33, 42, 47, 60, 61, 62, 96, 98, 101, 106, 173, 193 Vestibular Aqueduct, 60, 61, 62, 96, 106, 193 Vestibule, 165, 175, 188, 193 Vestibulocochlear Nerve, 162, 193 Veterinary Medicine, 150, 193 Viral, 142, 172, 191, 193 Virulence, 191, 193 Virus, 142, 172, 174, 187, 191, 193 Viscera, 189, 193 Visual field, 181, 187, 193 Vitreous, 23, 24, 165, 177, 187, 193 Vitreous Body, 165, 187, 193 Vitro, 89, 137, 193 Vivo, 193 Voltage-gated, 40, 41, 193 W White blood cell, 120, 160, 177, 178, 194 Windpipe, 191, 194 Womb, 192, 194 Wound Healing, 89, 194

202


X Xenograft, 160, 194 X-ray, 166, 167, 181, 186, 188, 194 Y Yeasts, 183, 194

Z Zona Pellucida, 64, 65, 194 Zygote, 167, 179, 194 Zymogen, 185, 194

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