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Hum Mol Genet. 2015 Feb 1;24(3):659-69. doi: 10.1093/hmg/ddu486. Epub 2014 Sep 25.

Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2.

Author information

1
Department of Human Genetics r.j.l.f.lemmers@lumc.nl.
2
Department of Biostatistics and.
3
Department of Human Genetics.
4
Department of Clinical Genetics and.
5
Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, San Sebastián, Spain.
6
Servicio de Genética, Hospital Virgen del Camino, Pamplona, Spain.
7
Servicio de Neurologia, Complejo Universitario de Navarra, Pamplona, Spain.
8
Institute of Medical Genetics, Cardiff University, Cardiff, UK.
9
Department of Pediatrics, University of Washington, Seattle, WA, USA.
10
Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
11
Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
12
Centre de Reference des Maladies Neuromusculaires, Nice, France.
13
Department of Neurology, University of Rochester, Rochester, NY, USA and.
14
Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.

Abstract

Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1-10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1-6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7-10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD.

PMID:
25256356
PMCID:
PMC4291246
DOI:
10.1093/hmg/ddu486
[Indexed for MEDLINE]
Free PMC Article

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