title: Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.
abstract: Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction-independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction-independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Richard J L F
authors.initials: RJ
authors.lastname: Lemmers
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Petek
authors.forename: Judit
authors.initials: J
authors.lastname: Balog
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Block
authors.forename: Gijs W E
authors.initials: GW
authors.lastname: Santen
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Amell
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van der Vliet
authors.forename: Rowida
authors.initials: R
authors.lastname: Almomani
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Straasheijm
authors.forename: Yvonne D
authors.initials: YD
authors.lastname: Krom
authors.forename: Rinse
authors.initials: R
authors.lastname: Klooster
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Johan T
authors.initials: JT
authors.lastname: den Dunnen
authors.forename: Quinta
authors.initials: Q
authors.lastname: Helmer
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Donlin-Smith
authors.forename: George W
authors.initials: GW
authors.lastname: Padberg
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Jessica C
authors.initials: JC
authors.lastname: de Greef
authors.forename: Annemieke M
authors.initials: AM
authors.lastname: Aartsma-Rus
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.forename: Galina N
authors.initials: GN
authors.lastname: Filippova
authors.forename: Bert
authors.initials: B
authors.lastname: Bakker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Miller
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000328:Adult; D000368:Aged; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D006239:Haplotypes; D040941:Heredity / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D009154:Mutation
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; C578241:SMCHD1 protein, human