Rearrangements within the facioscapulohumeral muscular dystrophy
locus: mechanism, timing and consequences.
Lemmers, R.
Citation
Lemmers, R. (2005, June 15). Rearrangements within the facioscapulohumeral muscular
dystrophy locus: mechanism, timing and consequences. Retrieved from
https://hdl.handle.net/1887/2699
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in theInstitutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/2699
CONTENTS
Chapter 1. Introduction
1.1 Facioscapulohumeralmuscular dystrophy
1.1.1 Clinicalcharacteristics 15
1.1.2 Genomic localization 15
1.1.3 Causalmolecular defect 16
1.1.4 Potentialmolecular mechanism 18 -FSHD gene within D4Z4 (DUX4)
-PEV model
-Long-distancecislooping model -Localchromatin alteration
1.1.5 Identification of FSHD genes 24 -FRG 1
-TUBB4Q,FRG2,andDUX4c 1.2Subtelomeric plasticity 4q35
1.2.1 General 26
1.2.2 Gene duplications 27
1.2.3 Duplications subtelomeric 4q35 genes 28 -FRG1-homologs
-TUBB4Q-homologs
-FRG2 and DUX4-homologs
1.2.4 Distal4q35 duplication 30
1.2.5 D4Z4 translocations 31
1.3Plasticity of repetitive DNA sequences
1.3.1 General 33
1.3.2 M odels for repeatinstability 34 1.3.3 Repeatinstability in human 35
1.3.4 Instability D4Z4 repeat 37
1.3.5 Timing of mitotic D4Z4 rearrangement 39
1.3.6 Repeathomogenization 44
1.3.7 Evolution of the D4Z4 repeat 46 1.4Implications of rearrangements for molecular diagnosis 49
M olecular diagnosis of FSHD
Lemmers RJLF,van der W ielen M JR,Bakker E,van der M aarelSM
1.5 Discussion
1.5.1 Molecular diagnosis FSHD 77
1.5.2 Mitotic rearrangement of D4Z4 contractions 81 Timing mitotic D4Z4 rearrangement
Rearrangement mechanism
1.5.3 Subtelomeric plasticity and the definition of the FSHD allele 82 Region distal to D4Z4
1.6 Future perspectives
1.6.1 Timing D4Z4 rearrangement 84
Analysis of mosaicism in gonadal cells D4Z4 methylation analysis
1.6.2 Interacting proteins 86
1.6.3 Transcription analysis D4Z4 87
1.6.4 Completing sequence 4qter and 10qter 89
1.6.5 Phenotype-genotype study 89
1.6.6 Genome-wide high throughput studies 90
1.7Summary of major findings 93
1.8 References 95
Chapter 2. 105
Hypomethylation of D4Z4 in 4q-linked and non-4q-linked FSHD
van Overveld PGM, Lemmers RJLF, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM
Nature Genetics 35/4 (2003) 315–317
Chapter 3. 115
FSHD is uniquely associated with one of the two variants of the 4q subtelomere
Lemmers RJLF, de Kievit P, Sandkuijl LA, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM
Nature Genetics 32/2 (2002) 235–236
Chapter 4. 123
Contractions of D4Z4 on 4qB subtelomeres do not cause FSHD
Chapter 5. 133
Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles Wohlgemuth M, Lemmers RJLF, van der Kooi EL, van der Wielen MJR, van Overveld PGM, Dauwerse H, Bakker E, Frants RR, Padberg GW, van der Maarel SM Neurology 61/7 (2003) 909–913 Chapter 6. 141
D4F104S1 deletion in FSHD: phenotype, size, and detection Lemmers RJLF, Osborn M, Haaf T, Rogers M, Frants RR, Padberg GW, Cooper DN, van der Maarel SM, Upadhyaya M Neurology 61/2 (2003) 178–183 Chapter 7. 151
Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in FSHD Lemmers RJLF, van Overveld PGM, Sandkuijl LA, Padberg GW, Frants RR, van der Maarel SM The American Journal of Human Genetics 75/1 (2004) 44–53 Chapter 8. 163
Somatic mosaicism in FSHD often goes undetected Lemmers RJLF, van der Wielen MJR, Bakker E, Padberg GW, Frants RR, van der Maarel SM Annals of Neurology 55/6 (2004) 845–850 Chapter 9. 171
Complete allele information in the diagnosis of FSHD by triple DNA analysis Lemmers RJLF, de Kievit P, van Geel M van der Wielen MJR, Bakker E, Padberg GW, Frants RR, van der Maarel SM Annals of Neurology 50/6 (2001) 816–819 Summary 179
Samenvatting 183
Bibliography 187
