title: Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2.
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.
authors.affiliation: Department of Human Genetics r.j.l.f.lemmers@lumc.nl.
authors.forename: Richard J L F
authors.initials: RJ
authors.lastname: Lemmers
authors.affiliation: Department of Biostatistics and.
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Goeman
authors.affiliation: Department of Human Genetics.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van der Vliet
authors.affiliation: Department of Clinical Genetics and.
authors.forename: Merlijn P
authors.initials: MP
authors.lastname: van Nieuwenhuizen
authors.affiliation: Department of Human Genetics.
authors.forename: Judit
authors.initials: J
authors.lastname: Balog
authors.affiliation: Department of Clinical Genetics and.
authors.forename: Marianne
authors.initials: M
authors.lastname: Vos-Versteeg
authors.affiliation: Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, San Sebastián, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Camano
authors.affiliation: Servicio de Genética, Hospital Virgen del Camino, Pamplona, Spain.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Ramos Arroyo
authors.affiliation: Servicio de Neurologia, Complejo Universitario de Navarra, Pamplona, Spain.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Jerico
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Rogers
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Miller
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.affiliation: Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Jan J G M
authors.initials: JJ
authors.lastname: Verschuuren
authors.affiliation: Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, San Sebastián, Spain.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Lopez de Munain Arregui
authors.affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
authors.forename: George W
authors.initials: GW
authors.lastname: Padberg
authors.affiliation: Centre de Reference des Maladies Neuromusculaires, Nice, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: Department of Neurology, University of Rochester, Rochester, NY, USA and.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.affiliation: Department of Clinical Genetics and.
authors.forename: Bert
authors.initials: B
authors.lastname: Bakker
authors.affiliation: Department of Human Genetics.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D014644:Genetic Variation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008840:Microfilament Proteins; D018895:Microsatellite Repeats; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D016601:RNA-Binding Proteins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C121257:DUX4L1 protein, human; C101270:FRG1 protein, human; C499414:FRG2 protein, human; D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C578241:SMCHD1 protein, human