Facioscapulohumeral Muscular Dystrophy (FSHD): Clinical Medicine and Molecular Cell Biology

FSHD Facioscapulohumeral Muscular Dystrophy Clinical Medicine and Molecular Cell Biology

FSHD Facioscapulohumeral Muscular Dystrophy Clinical Medicine and Molecular Cell Biology Edited by

Meena Upadhyaya and David N.Cooper Institute of Medical Genetics, Heath Park, Cardiff, UK

LONDON AND NEW YORK

© Garland Science/BIOS Scientific Publishers Limited, 2004, except for Chapter 13 where copyright is retained by the author. First published 2004 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/.” All rights reserved. No part of this book may be reprinted or reproduced or utilized in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. A CIP catalogue record for this book is available from the British Library. ISBN 0-203-48367-7 Master e-book ISBN

ISBN 0-203-59746-X (Adobe e-Reader Format) ISBN 18599 62440 (Print Edition) Garland Science/BIOS Scientific Publishers 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN, UK and 29 West 35th Street, New York, NY 10001-2299, USA World Wide Web home page: http://www.bios.co.uk/ This edition published in the Taylor & Francis e-Library, 2005. Garland Science/BIOS Scientific Publishers is a member of the Taylor & Francis Group Distributed in the USA by Fulfilment Center Taylor & Francis 10650 Toebben Drive Independence, KY 41051, USA Toll Free Tel.: +1 800 634 7064; E-mail [email protected] Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel.: +1 877 226 2237; E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House, North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424; E-mail: [email protected] Library of Congress Cataloguing in Publication Data FSHD facioscapulohumeral muscular dystrophy: clinical medicine and molecular cell biology/edited by Meena Upadhyaya and David N Cooper. p. cm. Includes bibliographical references and index. ISBN 1-85996-244-0 1. Facioscapulohumeral muscular dystrophy. I. Upadhyaya, M. (Meena) II. Cooper, David N., Dr. RC935.M7F74 2004 616.7′47—dc22 2004003241 Production Editor: Catherine Jones

Contents

Abbreviations Contributors

viii x

Acknowledgements

xiii

Dedication

xiv

Foreword

xvi

1. Introduction and overview of FSHD M.Upadhyaya and D.N.Cooper 2. Facioscapulohumeral muscular dystrophy: historical background and literature review M.Rogers 3. Facioscapulohumeral muscular dystrophy: a clinician’s experience G.W.Padberg 4. Mapping of the FSHD gene and the discovery of the pathognomonic deletion R.R.Frants, L.A.Sandkuijl, S.M.van der Maarel and G.W.Padberg 5. Identification and characterization of candidate genes in FSHD region S.van Koningsbruggen, R.R.Frants, S.M.van der Maarel 6. Evolution and structural organization of the homeoboxcontaining repeat D4Z4 J.E.Hewitt 7. Subtelomeric exchange between 4q and 10q sequences R.R.Frants and S.M.van der Maarel 8. Genomic analysis of the subtelomeric regions of human chromosomes 10q and 4q: relevance to FSHD M.van Geel and J.E.Hewitt

1 17

40

54

63

83

96 108

9. The DUX gene family and FSHD F.Coppée, C.Mattéotti, E.Ansseau, S.Sauvage, I.Leclercq, A.Leroy, A.Marcowycz, C.Gerbaux, D.Figlewicz, H.Ding and A.Belayew 10. Facioscapulohumeral muscular dystrophy (FSHD): a disorder of muscle gene repression R.Tupler and D.Gabellini 11. Genotype-phenotype relationships in FSHD P.Lunt, M.Upadhyaya and M.C.Koch 12. Mosaicism and FSHD P.G.M.van Overveld, R.R.Frants and S.M.van der Maarel 13. Retinal vascular abnormalities in FSHD: a therapeutic message; clues to pathogenesis R.B.Fitzsimons 14. Unusual clinical features associated with FSHD Y.K.Hayashi 15. Molecular diagnosis of FSHD R.J.LF.Lemmers, M.J.R.van der Weilen, E.Bakker and S.M.van der Maarel 16. FSHD myoblasts: in vitro studies D.A.Figlewicz, K.Barrett, A.Haefele Leskovar, J.R.Forrester, J.E.Sowden and R.Tawil 17. Exploring hypotheses about the molecular aetiology of FSHD: loss of heterochromatin spreading and other long-range interaction models M.Ehrlich 18. Histological, immunological, molecular and ultrastructural characteristics of FSHD muscle M.T.Rogers, M.Upadhyaya and C.A.Sewry 19. Linkage analysis in non-chromosome 4-linked FSHD K.Bastress, J.Stajich, J.Gilbert and M.Speer 20. Facioscapulohumeral muscular dystrophy: gender differences and genetic counselling in a complex disorder M.Manuela de Oliveira Tonini and M.Zatz 21. Genetic counselling for facioscapulohumeral muscular dystrophy (FSHD) P.Lunt

119

140

155 173

191

201 215

249

271

293

314

324

340

22. Sarcolemmal reorganization in FSHD P.Reed, N.C.Porter, J.Strong, P.W.Luther, K.M.Flanigan and R.J.Bloch 23. Expression profiling in FSHD S.T.Winokur and Y.-W.Chen 24. Therapeutic trials and medical management in FSHD R.Tawil and R.C.Griggs

356

370 389

Appendices AppendixI: The FSH Society AppendixII: The Muscular Dystrophy Campaign: pioneering research, providing care AppendixIII: The Association Française contre les Myopathies Index

396 402 404 405

Abbreviations

ALS

amyotrophic lateral sclerosis

BLAST

basic local alignment search tool

BMD

Becker muscular dystrophy

cdk

cyclin-dependent kinase

cDNA

complementary DNA

CK

creatine kinase

DMD

Duchenne muscular dystrophy

DFC

dense fibrillar component

ECG

electrocardiogram

EDMD

Emery-Dreifuss muscular dystrophy

EMSA

electrophoretic mobility shift assay

EST

expressed sequence tag

FC

fibrillar centre

FGF

fibroblast growth factor

FIGE

field inversion gel electrophoresis

FISH

fluorescent in situ hybridization

FSHD

facioscapulohumeral muscular dystrophy

FSLD

facioscapulolimb dystrophy

GC

genetic counselling

GC

granular component

HMG

high mobility group

IEF

isoelectric focusing

LCR

locus control region

LGMD

limb girdle muscular dystrophy

MHC

myosin heavy chain

MRF

myogenic regulatory factor

MRI

magnetic resonance imaging

NF1/2

neurofibromatosis type 1/2

NLS

nuclear localization signal

ORF

open reading frame

PBL

peripheral blood lymphocyte

PCR

polymerase chain reaction

PEO

progressive external ophthalmoplegia

PEV

position effect variegation

PFGE

pulsed-field gel electrophoresis

PRE

polycomb response element

PTPC

permeability transition pore complex

RFLP

restriction fragment length polymorphism

RT

reverse transcription

SCARMD

severe childhood autosomal recessive muscular dystrophy

SMA

spinal muscular atrophy

snRNA

small nuclear RNA

snoRNA

small nucleolar RNA

snRNP

small nuclear ribonuclear protein

SPECT

single-photon-emission computed tomography

SSCP

single-strand conformational polymorphism

STS

sequence tagged site

TRE

trithorax response element

VNTR

variable number tandem repeat

Contributors

Ansseau, Eugénie Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Bakker, Bert Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands Barrett, Kathy Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, PO Box 673, Rochester NY 14642, USA Bastress, Kristen Duke University Medical Center, Box 3445, Durham NC 27710, USA Belayew, Alexander Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Bloch, Robert Department of Physiology and Neurology, University of Maryland School of Medicine, Baltimore MD 21201, USA Chen, Yi-Wen Center for Genetic Medicine Children’s National Medical Center, 111 Michigan Avenue NW, Washington DC 20010, USA Cooper, David N. Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK Coppée, Frédérique Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Ding, Hao Samuel Lunenfeld Research Institute, Mount Sinaï Hospital, Toronto, Ontario M5G 1X5, Canada Ehrlich, Melanie Tulane Medical School, 1430 Tulane Avenue, New Orleans LA 70112–2699, USA Figlewicz, Denise Department of Neurology, University of Michigan Medical School, Ann Arbor MI 48109-0588, USA Fitzsimons, Robin 229 Macquarie Street, Sydney, New South Wales 2000, Australia Flanigan, Kevin M. Eccles Institute of Human Genetics, 15 North 2030 East, University of Utah, Salt Lake City, UT 84112, USA Forrester, James R. Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, PO Box 673, Rochester NY 14642, USA Frants, Rune R. Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands Gabellini, Davide Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts, 373 Plantation Street, Worcester MA 01606, USA Gerbaux, Cécile Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone, 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Gilbert, John Duke University Medical Center, Box 3445, Durham NC 27710, USA

Griggs, Robert Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, PO Box 673, Rochester NY 14642, USA Harper, Peter Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK Hayashi, Yukiko Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan Hewitt, Jane Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, Nottingham, NG7 2UH, UK Koch, Manuela Institut für Humangenetik, Abteilung 1, Der Philipps-Universität Marburg, Bahnhofstrasse 7A, 35037 Marburg, Germany Leclercq, India Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Lemmers, Richard, Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands Leroy, Axelle Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Haefele Leskovar, Amanda Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, PO Box 673, Rochester NY 14642, USA Lunt, Peter Department of Clinical Genetics, Institute of Child Health, Bristol Children’s Hospital, St Michael’s Hill, Bristol, BS2 8DT, UK Luther, Paul W. Department of Physiology and Neurology, University of Maryland School of Medicine, Baltimore MD 21201, USA Marcowycz, Aline Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Mattéotti, Christel Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Padberg, George Department of Neurology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands Porter, Neil C. Department of Physiology and Neurology, University of Maryland School of Medicine, Baltimore MD 21201, USA Reed, Patrick Department of Physiology and Neurology, University of Maryland School of Medicine, Baltimore MD 21201, USA Rogers, Mark T. Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK Sauvage, Sébastien Laboratory of Molecular Biology, Université de Mons-Hainaut, Pentagone 3A, 6 Avenue du Champs de Mars, B-7000 Mons, Belgium Sewry, Caroline Robert Jones & Agnes Hunt Hospital NHS Trust, Gabowen, Oswestry SY10 7AU,UK Speer, Marcy Duke University Medical Center, Box 3445, Durham NC 27710, USA Sowden, Janet E. Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, PO Box 673, Rochester NY 14642, USA Stajich, Jeffrey Duke University Medical Center, Box 3445, Durham NC 27710, USA Strong, John Department of Physiology and Neurology, University of Maryland School of Medicine, Baltimore MD 21201, USA de Oliveira Tonini, Maria Manuela, Departamento de Biologia Instituto de Biociências, Universidade de São Paulo/USP, São Paulo, Brazil

Tawil, Rabi Department of Neurology, University of Rochester School of Medicine, 601 Elmwood Avenue, PO Box 673, Rochester NY 14642, USA Tupler, Rosella Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts, 373 Plantation Street, Worcester MA 01606, USA Upadhyaya, Meena Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK van der Maarel, Silvere Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands van Geel, Michael Department of Human genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo NY 14263, USA van Koningsbruggen, Silvana Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands van Overveld, Petra Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands van der Weilen, M J R Leiden University Medical Centre, Department of Human Genetics, Wassenaarsweg 72, 2300 RA Leiden, The Netherlands Winokur, Sara 240 D Medical Sciences I, Department of Biological Chemistry, University of California, Irvine CA 92697, USA Zatz, Mayana Departamento de Biologia Inst. de Biociências Universidade de São Paulo/USP, São Paulo, Brazil.

Acknowledgements

MU wishes to thank Professor Peter Harper for introducing her to FSHD research. We thank past and present colleagues and collaborators including Peter Lunt, Mansoor Sarfarazi, Wendy Broadhead, Duncan Shaw, Russell Snell, David Ravine, Julia Farnham, Mike Owen, Jo Ikeda, John MacMillan, Mike Osborn, Julie Maynard, Mark Rogers, Jane Fenton-May, Duran Ustek, Piraye Serdaroglu, Mo MacDonald and Katie Wiseman. We also thank the Wellcome Trust, the Muscular Dystrophy Campaign and the Association Française contre les Myopathies for their financial support and perhaps most important of all, the patients and their families for their understanding and enthusiastic cooperation.

Dedication

To Rachna and the memory of Krishna.

Foreword

Peter S.Harper

Facioscapulohumeral muscular dystrophy (FSHD) is both a fascinating and a challenging disorder for researchers as well as for clinicians. As one of the most frequent muscular dystrophies of adult life, it has long deserved a book specifically devoted to it; there is far too much important information to fit readily into a single chapter or chapter section of a more general book on muscle disease, as has been the case until now. So this book on FSHD is both welcome and necessary, since without a single comprehensive source, it is difficult for those involved in the disorder to obtain a clear and balanced account of its different aspects. Clinicians and clinical geneticists will find this a source of real practical value, especially when faced with difficult diagnostic dilemmas and complex genetic counselling situations. Laboratory scientists will also find the clinical sections helpful, often throwing light on aspects of more basic work that would otherwise seem puzzling. For those involved in FSHD research, this book brings together all the main strands of current work, with the key workers across the world all contributing to it. The basic mechanisms underlying the condition are still elusive, but promise to make fundamental contributions to biology, as has already occurred with a range of other neuromuscular disorders. The FSHD research community is an active, collaborative and innovative one, and there are still many challenges ahead for it. So it is of the greatest value to have this book to give a full and clear picture of our current knowledge, as a platform on which future research can be based. Meena Upadhyaya, deeply involved in FSHD research for many years, and her close colleague David Cooper, are to be congratulated in providing us with a synthesis that will not only be of practical help to clinicians and scientists, but should also encourage other workers to contribute to the still unsolved challenges for our fuller understanding of this important condition.

1. Introduction and overview of FSHD

Meena Upadhyaya, and David N.Cooper FSHD Facioscapulohumeral Muscular Dystrophy: Clinical Medicine and Molecular Cell Biology, edited by Meena Upadhyaya and David N.Cooper. © 2004 Garland/BIOS Scientific Publishers Limited, Abingdon.

1.1 Introduction FSHD is a unique genetic disorder. For a long time, the molecular basis of this condition was enigmatic. Indeed, some 13 years elasped between the mapping of the chromosomal location of the gene and deducing the nature of the unique molecular mechanism underlying the disease. The last decade has thus been an extremely exciting one for FSHD research (Figure 1.1). During this time it is clear that there has been a very significant increase in our knowledge of the molecular genetics of FSHD. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited neuromuscular condition, after Duchenne and myotonic muscular dystrophies (Upadhyaya and Cooper, 2002). FSHD is an autosomal dominant inherited disorder characterized by progressive muscle weakness and involving atrophy of the muscles of the face, upper arm and shoulder girdle (see Chapters 2 and 3). General muscle weakness and atrophy may eventually involve musculature of the pelvic girdle and the foot extensor. Early onset of the disease is usually associated with the development of the most severe forms of the disorder (Lunt and Harper, 1991; Padberg, 1998). Disease onset is unusual before the age of 10, however, being observed in fewer than 5% of patients, in whom it is associated with significant facial weakness. The majority of patients only develop symptoms later during the second decade of life. Both retinal vasculopathy and high-tone deafness may be seen as part of FSHD (see Chapter 13). However, clinically significant deafness is rare in adult FSHD. In some families, the affected individuals share many of the clinical features of FSHD but show no evidence of facial muscle involvement, even in the most severely affected patients. These ‘scapulohumeral muscular dystrophy’ families display an autosomal dominant mode of inheritance, and it has been suggested that they may form part of the FSHD disease spectrum (Jardine et al., 1994; Tawil et al., 1995; Felice et al., 2000). In some FSHD families, the disease is associated with mental retardation and epilepsy (see Chapter 14).

FSHD facioscapulohumeral muscular dystrophy

2

Figure 1.1 The total annual number of publications relating to FSHD retrieved from PubMed (NCBI), from 1980. 1.2 Gene mapping studies The FSHD locus was genetically mapped to chromosome 4q35 (Upadhyaya et al., 1990; Wijmenga et al., 1990) where it is closely linked to the complex locus D4F104S1 (Figure 1.2) identified by Southern analysis using probe p13E-11 (Wijmenga et al., 1992). Details of the mapping studies are given in Chapter 4. There is some evidence for genetic heterogeneity in FSHD. Although the vast majority of large FSHD families can be demonstrably linked to 4q35, a small number of classical FSHD families have been excluded from this location (Gilbert et al., 1993). A genomic position for this second disease locus, tentatively designated FSHD1B, has still to be identified (see Chapter 19). 1.2.1 DNA rearrangements associated with D4F104S1 and D4Z4 repeats Probe p13E-11 (D4F104S1) identifies an EcoRI restriction fragment, with homology to both 4q35 and 10q26. In FSHD patients, one fragment derived from one of the two homologous chromosomes 4, is usually smaller than 35 kb. Studies in suitably informative FSHD families have demonstrated the 4q35 component of the D4F104S1 locus to be the closest marker to the disease gene. Sequence analysis of the entire D4F104S1 locus has shown that p13E-11 identifies a single copy genomic sequence that is located immediately proximal to an array of tandem repeat units. It is variation in the exact number of individual repeats, in each of the 4q35- and 10q26-derived repeat arrays,

Introduction and overview of FSHD

3

that constitutes the polymorphic element of the D4F104S1 variable number tandem repeat (VNTR) and of the two specific EcoRI restriction sites which define this VNTR; one site is located proximal to the sequence homologous to the p13E-11 probe, whereas the second is situated immediately distal to the tandem repeat array (see Figure 1.2).

Figure 1.2 Restriction map of the FSHD candidate region at 4q35: Relative positions of FRG1, TUBB4Q, FRG2, D4F104S1 (p13E11) and D4Z4. The EcoRI fragment detected by probe p13E11 predominantly comprises an array of 3.3 kb tandem repeats that have a copy number of 12– 100 in normal controls and usually