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

by Cooper; David

• ISBN13: 9781859962442
• ISBN10: 1859962440
• Edition: 1st
• Format: Hardcover
• Copyright: 2004-06-15
• Publisher: Taylor & Franci

Summary

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder involving slowly progressive muscle degeneration in which the muscles of the face, shoulder blades and upper arms are among the most severely affected. It is the third most common inherited muscular dystrophy, affecting 1 in 20,000. The search for the molecular basis of the disease is of interest to all genetic researchers, involving a deletion outside a coding region resulting in over-expression of adjacent genes. This volume summarizes the current understanding of the disorder, including clinical, molecular and therapeutic aspects.

Table of Contents

Abbreviations	xv
Contributors	xvii
Acknowledgements	xx
Dedication	xxi
Foreword	xxiii
1. Introduction and overview of FSHD	1	(16)
M. Upadhyaya and D.N. Cooper
Introduction	1	(1)
Gene mapping studies	2	(3)
DNA rearrangements associated with D4F10451 and D4Z4 repeats	2	(2)
D424 repeats	4	(1)
Sequence homology and genetic recombination between 4q35 and 10q26	5	(1)
Somatic mosaicism	5	(1)
The genotype/phenotype relationship in FSHD	6	(1)
Gender bias	6	(1)
Molecular diagnosis of FSHD	7	(1)
FSHD muscle biochemistry and physiology	8	(1)
The search for the FSHD gene	8	(1)
Potential gene sequences within the FSHD candidate region	9	(1)
Methylation studies	9	(1)
Expression studies in the FSHD candidate region	10	(1)
Therapy	10	(1)
Possible disease mechanism	11	(1)
Transcriptional derepression	11	(1)
The FSHD enigma	12	(1)
References	13	(4)
2. Facioscapulohumeral muscular dystrophy: historical background and literature review	17	(24)
M. Rogers
Historical aspects	17	(3)
Clinical aspects	20	(13)
Distribution of affected muscles	20	(4)
Age of onset	24	(1)
Penetrance	25	(1)
Gender differences	26	(1)
Hearing impairment	27	(1)
Coats' disease and vascular retinopathy	28	(2)
Cardiac involvement	30	(2)
Early onset and rare features of FSHD	32	(1)
Summary	33	(1)
References	33	(8)
3. Facioscapulohumeral muscular dystrophy: a clinician's experience	41	(14)
G.W. Padberg
Historical notes	41	(1)
Clinical picture	41	(6)
Non-muscular features	47	(1)
Infantile facioscapulohumeral muscular dystrophy	47	(1)
Age at onset of the disease	48	(1)
Gender and generation effects in FSHD	49	(1)
Course of the disease	49	(1)
Prevalence and fitness	50	(1)
Penetrance	50	(1)
Therapies	50	(1)
References	51	(4)
4. Mapping of the FSHD gene and the discovery of the pathognomonic deletion 55
R.R. Frants, L.A. Sandkuijl, S.M. van der Maarel and G.W. Padberg
Introduction	55	(1)
Gene mapping prior to the advent of DNA polymorphisms	55	(1)
Gene mapping with DNA polymorphisms	56	(1)
Microsatellite markers; the first linkage success	57	(1)
Probe p13E-11; the hallmark of FSHD success	57	(1)
Rearrangement in de novo FSHD patients	58	(1)
FSHD mutation caused by rearrangement of the 3.3 kb Kpnl repeat (D4Z4)	59	(1)
Does the FSHD D4Z4 array modulate long-range gene expression?	59	(1)
References	60	(5)
5. Identification and characterization of candidate genes in FSHD region	65	(20)
S. van Koningsbruggen, R.R. Frants, S.M. van der Maarel
Position effect as the underlying mechanism in FSHD	65	(2)
The D4Z4 repeat and Dux4: the complete story?	67	(1)
Gene search strategies in the FSHD candidate region	67	(3)
Direct genomic analysis	68	(1)
Exon trapping	69	(1)
cDNA selection	70	(1)
Direct sequence analysis	70	(1)
The most promising candidate genes for FSHD	70	(7)
FRG1, a tightly conserved nuclear protein	70	(4)
TUBB4Q, a pseudogene?	74	(1)
FRG2, a muscle-specific transcript	75	(1)
ANTI, a muscle-specific mitochondrial protein	76	(1)
Other candidate genes	77	(1)
Concluding remarks	78	(1)
References	78	(7)
6. Evolution and structural organization of the homeobox-containing repeat D4Z4	85	(12)
J.E. Hewitt
Introduction	85	(1)
Organization of the D4Z4 repeat	85	(2)
D4Z4-related sequences in the human genome	87	(1)
Conservation of D4Z4 in other organisms	88	(5)
D4Z4 orthologues in primates	88	(1)
Further analysis of the evolution of D4Z4; the potential of genome sequence projects	89	(4)
Conclusions	93	(1)
References	93	(4)
7. Subtelomeric exchange between 4q and 97 10q sequences	97	(10)
R.R. Frants and S.M. van der Maarel
Introduction	97	(1)
The second p13E-11 locus maps to 10g26	97	(1)
Differential detection of the two loci	98	(1)
'Cross-talk' between the subtelomeres of 4q and 10q	98	(2)
Prevalence of interchromosomal exchange	100	(1)
Repeat array configurations	101	(1)
Functional consequences	102	(1)
Repeat size distribution	102	(1)
FSHD-sized repeat arrays	103	(1)
References	104	(3)
8. Genomic analysis of the subtelomeric regions of human chromosomes 10q and 4q: relevance to FSHD	107	(10)
M. van Geel and J.E. Hewitt
Introduction	107	(1)
Genomic analysis of the FSHD locus chromosome 4qter	107	(1)
A polymorphism at the 4q telomere	108	(1)
Extensive sequence homology between chromosomes 4qter and 10gter	108	(3)
The 4q35 and 10g26 3.3 kb repeats	109	(1)
Sequence homology between the 4q and 10q subtelomeres	110	(1)
Sequence homology between chromosomes 4q35 and 10g26 extends proximal to the 3.3 kb repeats	111	(1)
Relationship of 4qter to other telomeres	111	(1)
Evolution of 4gter	111	(2)
FSHD is only associated with the 4qA allele	113	(1)
Concluding remarks	113	(1)
References	114	(3)
9. The DUX gene family and FSHD	117	(18)
F. Coppée, C. Mattéotti, E. Ansseau, S. Sauvage, I. Leclercq, A. Leroy, A. Marcowycz, C. Gerbaux, D. Figlewicz, H. Ding and A. Belayew
Introduction	117	(1)
Cloning of a gene promoter homologous to part of the D4Z4 unit	118	(1)
Expression of double homeobox (DUX) genes located within 3.3 kb elements not linked to FSHD	119	(2)
Expression in vivo of a DUX1 protein with properties of a transcription factor	121	(1)
A putative DUX4 gene in the D4Z4 units of the FSHD locus	121	(2)
Expression of the DUX4 protein	123	(3)
A function for the DUX4 protein	126	(1)
A putative DUX4c gene centromeric to D4Z4	126	(3)
Discussion and conclusions	129	(2)
References	131	(4)
10. Facioscapulohumeral muscular dystrophy (FSHD): a disorder of muscle gene repression	135	(16)
R. Tupler and D. Gabellini
Introduction	135	(1)
D4Z4 contains heterochromatic elements	136	(1)
The FSHD region on chromosome 4q35 contains genes and pseudogenes	137	(1)
Haploinsufficiency of distal 4q does not cause facioscapulohumeral muscular dystrophy	138	(1)
Expression of 4q35 genes is up-regulated in FSHD dystrophic muscle	138	(1)
Detection of a nuclear activity that binds to D4Z4	139	(2)
A new model for FSHD	141	(2)
Open questions	143	(1)
References	144	(7)
11. Genotype-phenotype relationships in FSHD	151	(18)
P. Lunt, M. Upadhyaya and M.C. Koch
Introduction	151	(1)
What are the variations in phenotype and genotype against which any relationship between these can be gauged?	152	(1)
Phenotypic parameters studied in FSHD	152	(1)
Genotypic parameters against which the phenotypic parameters can be assessed	152	(1)
Correlations and exceptions	153	(2)
The broad correlations	153	(1)
Emerging exceptions/cautions	154	(1)
Null effects	154	(1)
Unknowns	154	(1)
Evidence for correlations	155	(8)
Increasing clinical effect with reducing residual fragment size	155	(1)
Infantile-onset cases and wider clinical effects	156	(1)
Male:female difference	157	(1)
New mutation and mosaicism	157	(2)
Comparison of clinical and genetic properties between new mutation and familial cases	159	(1)
Three categories of family presentation of FSHD (types I, II, III)	159	(2)
Blnl-sensitive alleles and the type A and B polymorphism	161	(1)
Emerging exceptions to the overall correlations	161	(2)
Fitting severity variation and correlation with molecular models	163	(2)
Proposed models	163	(1)
Transcriptional derepression	164	(1)
Understanding clinical variation in FSHD	164	(1)
References	165	(4)
12. Mosaicism and FSHD	169	(16)
P.G.M. van Overveld, R.R. Frants and S.M. van der Maarel
Introduction	169	(1)
Mosaicism explained	169	(2)
Somatic mosaicism	171	(1)
Germline mosaicism	172	(1)
Somatic and germline mosaicism in FSHD	173	(3)
Implications for genetic counseling and research	176	(2)
Summary	178	(2)
References	180	(5)
13. Retinal vascular abnormalities in FSHD: a therapeutic message; clues to pathogenesis	185	(12)
R.B. Fitzsimons
Introduction	185	(1)
Retinal disease and FSHD	186	(3)
Background and therapeutics	186	(2)
Male sex bias in sporadic Coats' disease and in FSHD	188	(1)
FSHD muscle and retinal diseases are both highly asymmetric	188	(1)
Retinal disease and pathogenesis	189	(2)
Norrie disease and Coats' disease can both be caused by mutation of a TGF-beta protein ('norrin')	189	(2)
References	191	(6)
14. Unusual clinical features associated with FSHD	197	(14)
Y.K. Hayashi
Introduction	197	(1)
Early-onset form of FSHD	197	(1)
Unusual muscle involvement observed in FSHD patients	198	(4)
Facial-sparing scapular myopathy	198	(1)
Tongue atrophy	199	(1)
Head drooping	199	(1)
Abdominal muscle involvement and lumbar lordosis	199	(2)
Limb girdle type muscle weakness	201	(1)
Distal myopathy	201	(1)
Muscle pain	202	(1)
Association with other types of neuromuscular disorders	202	(1)
Cardiac involvement	203	(1)
Respiratory failure	203	(1)
Central nervous system involvement	204	(1)
Psychopathological and emotional examination	204	(1)
Hearing loss	205	(1)
Retinopathy	205	(1)
References	206	(5)
15. Molecular diagnosis of FSHD	211	(24)
R.J.L.F. Lemmers, M.J.R. van derWeilen, E. Bakker and S. M. van der Maarel
Introduction	211	(1)
General	212	(1)
10g26 homology	212	(1)
4;10 D4Z4 translocations	213	(2)
Hybrid D4Z4 repeat arrays	215	(1)
D4F10451 deletion	216	(5)
Short non-pathogenic allels	221	(1)
Mosaicism in FSHD	222	(2)
Notl-digest for chromosomal assignment	224	(1)
Bg/ll/Blnl dosage test	224	(2)
Standard FSHD diagnostics	226	(2)
DNA preparation	228	(1)
Specificity and sensitivity	229	(1)
Concluding remarks	229	(1)
References	230	(5)
16. FSHD myoblasts: in vitro studies	235	(18)
D.A. Figlewicz, K. Barrett, A. Haefele Leskovar, J.R. Forrester, J.E. Sowden and R. Tawil
Introduction	235	(1)
Myoblast morphology and replication	236	(1)
Characterization of myoblasts	236	(1)
Myoblast studies - cell biology	236	(1)
Oxidative stress	237	(2)
Cell survival studies in FSHD myoblasts	238	(1)
Question of cell cycle/premature differentiation/premature senescence	239	(7)
Intracellular redox state	239	(2)
Senescence in FSHD myoblasts	241	(1)
Cell cycle dysregulation/p21 detection in FSHD - a connection with oxidative stress?	241	(4)
Senescence in FSHD myoblasts - replicative or premature	245	(1)
Discussion/future directions	246	(2)
References	248	(5)
17. Exploring hypotheses about the molecular aetiology of FSHD: loss of heterochromatin spreading and other long-range interaction models	253	(24)
M. Ehrlich
Introduction	253	(2)
Background and complicating factors in studies of the molecular genetic aetiology of FSHD	255	(5)
Large size of D4Z4 repeat array and associated FSHD candidate region and the importance of maintaining the natural spacing of FSHD-related DNA elements at 4q35	255	(1)
Homology between 4q35 and 10g26	256	(1)
Homology between the D4Z4 subregions and various chromosomes	257	(1)
Homology between sequences proximal and distal to the D4Z4 array in 4g35/10g26 and various other chromosomal regions	258	(1)
Tissue-specific and age-specific nature of the disease	259	(1)
Molecular clues about genetic aspects of FSHD	260	(2)
Difficulties with the PEV model for FSHD	262	(2)
Other molecular genetic models for FSHD	264	(5)
General considerations	264	(1)
The long-distance looping for transcriptional activation in FSHD	265	(4)
Conclusions	269	(1)
References	270	(7)
18. Histological, immunological, molecular and ultrastructural characteristics of FSHD muscle	277	(22)
M.T. Rogers, M. Upadhyaya and C.A. Sewry
Introduction	277	(1)
Patient characteristics	278	(1)
Biopsy site	279	(1)
Sample handling	279	(2)
Immunoblotting (western blot) studies	281	(1)
Ultrastructure	282	(1)
Molecular analysis of FSHD	282	(1)
Light microscopy	282	(3)
Immunocytochemistry	285	(2)
Electron microscopy	287	(6)
Myofibrillar structure	287	(1)
Mitochondria	288	(2)
Basal lamina	290	(1)
Glycogen	291	(2)
Conclusion	293	(1)
References	294	(5)
19. Linkage analysis in non-chromosome 4-linked FSHD	299	(10)
K. Bastress, J. Stajich, J. Gilbert and M. Speer
Introduction	299	(1)
Facioscapulohumeral muscular dystrophy is genetically heterogeneous	299	(2)
FSHD1B and FSHD1A are phenotypically indistinguishable	301	(2)
Is FSHD1B allelic to other proximal myopathies?	303	(1)
Status of linkage studies in FSHD1B	304	(1)
Candidate gene studies in non-chromosome 4-linked FSHD	305	(1)
Expression studies in FSHD1B	305	(1)
Summary	306	(1)
References	306	(3)
20. Facioscapulohumeral muscular dystrophy: gender differences and genetic counselling in a complex disorder	309	(16)
M. Manuela de Oliveira Tonini and M. Zatz
Introduction	309	(1)
Abortive or asymptomatic cases	309	(1)
Gender differences: reports from the premolecular era	310	(1)
Gender differences following molecular analysis	311	(1)
Recent analysis of a larger Brazilian sample	312	(1)
Phenotypic severity versus fragment size	313	(2)
Asymptomatic carriers	315	(1)
Parental transmission	316	(1)
Gender differences	316	(1)
Clinical anticipation	317	(1)
Is clinical anticipation influenced by the gender of the transmitting parent?	318	(1)
How to relate clinical and genealogical observations and new molecular findings	319	(1)
Genetic counselling and prenatal diagnosis	320	(1)
References	321	(4)
21. Genetic counselling for facioscapulohumeral muscular dystrophy (FSHD)	325	(16)
P. Lunt
Introduction	325	(2)
What are the common genetic situations and questions encountered in the genetic clinic in relation to FSHD?	327	(2)
Patient themselves affected with FSHD (or affected child)	327	(1)
Patient themselves affected with FSHD, or affected child or relative	328	(1)
Specific genetic situations	329	(8)
Typical classic familial case - known affected	329	(2)
Typical dominant family history: consultand themselves clinically unaffected	331	(3)
Mild presentation with or without a known family history	334	(1)
Severe case in a relative (i.e. in a sib, or in other relative), or parents of a severely affected child (i.e. with same set of parents, or with new partner) or severe case in consultand	335	(2)
References	337	(4)
22. Sarcolemmal reorganization in FSHD	341	(12)
P. Reed, N. C. Porter, J. Strong, P.W. Luther, K.M. Flanigan and R.J. Bloch
Introduction	341	(1)
Sarcolemmal alterations in FSHD	342	(3)
Sarcolemmal involvement in FSHD and other dystrophies	345	(1)
Conclusion and model	346	(2)
Future directives	348	(1)
References	348	(5)
23. Expression profiling in FSHD	353	(18)
S.T. Winokur and Y.-W. Chen
Introduction	353	(2)
Deletion of D4Z4 in FSHD	353	(1)
Chromatin structure of D4Z4	354	(1)
Regulation of gene expression	354	(1)
Genome-wide expression profiling	355	(1)
Overview	355	(1)
Oligonucleotide arrays	355	(1)
cDNA arrays	356	(1)
Expression profiling of FSHD muscle	356	(6)
Cell cycle and differentiation genes	356	(2)
Common changes in muscular dystrophy	358	(1)
Position effect vaiegation	359	(1)
4q35 regional gene expression	360	(2)
Myoblasts as models for differentiation	362	(3)
Myogenesis	362	(1)
Gene expression in FSHD myoblasts	362	(1)
Protein expression in FSHD myoblasts	363	(1)
Nuclear localization studies	364	(1)
Summary	365	(1)
References	366	(5)
24. Therapeutic trials and medical management in FSHD	371	(8)
R. Tawil and R.C. Griggs
Introduction	371	(1)
Therapeutic trials in FSHD	372	(2)
Corticosteroids	372	(1)
Albuterol	372	(1)
Creatinine monohydrate	373	(1)
Medical management	374	(1)
Assistive devices	374	(1)
Surgical interventions	374	(1)
Role of exercise	374	(1)
Pain	375	(1)
References	375	(4)
Appendices	379	(10)
Appendix I: The FSH Society	379	(6)
Appendix II: The Muscular Dystrophy Campaign: pioneering research, providing care	385	(2)
Appendix Ill: The Association Francaise contre les Myopathies	387	(2)
Index	389