Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2

• Published in: Nature genetics Vol. 44; no. 12; pp. 1370 - 1374
• Main Authors: Lemmers, Richard J L F, Tawil, Rabi, Petek, Lisa M, Balog, Judit, Block, Gregory J, Santen, Gijs W E, Amell, Amanda M, van der Vliet, Patrick J, Almomani, Rowida, Straasheijm, Kirsten R, Krom, Yvonne D, Klooster, Rinse, Sun, Yu, den Dunnen, Johan T, Helmer, Quinta, Donlin-Smith, Colleen M, Padberg, George W, van Engelen, Baziel G M, de Greef, Jessica C, Aartsma-Rus, Annemieke M, Frants, Rune R, de Visser, Marianne, Desnuelle, Claude, Sacconi, Sabrina, Filippova, Galina N, Bakker, Bert, Bamshad, Michael J, Tapscott, Stephen J, Miller, Daniel G, van der Maarel, Silvère M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2012; Nature Publishing Group
• Subjects: 631/208/176; 631/208/2489/144; 692/699/1670/1669; Adult; Aged; Agriculture; Allelomorphism; Animal Genetics and Genomics; Biological and medical sciences; Biomedicine; Cancer Research; Chromosomal Proteins, Non-Histone - genetics; Chromosomes; Chromosomes, Human, Pair 18 - genetics; CpG Islands - genetics; Development Biology; Diseases of striated muscles. Neuromuscular diseases; DNA Methylation - genetics; Dystrophy; Epigenesis, Genetic; Facioscapulohumeral muscular dystrophy; Female; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Health aspects; Heredity - genetics; Homeodomain Proteins - genetics; Human Genetics; Humans; letter; Life Sciences; Male; Medical sciences; Middle Aged; Muscular Dystrophy, Facioscapulohumeral - genetics; Mutation; Neurology; Physiological aspects; Proteins; France; United States; Netherlands; Nervous system diseases; Neuromuscular diseases; Allele; Inheritance(genetics); Mutation; Facioscapulohumeral; Muscular dystrophy; Genetic disease
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2454

Silvère van der Maarel, Stephen Tapscott, Daniel Miller and colleagues show that digenic inheritance of a mutation in SMCHD1 and a chromosome 4 haplotype permissive for DUX4 mRNA polyadenylation causes fascioscapulohumeral dystrophy type 2. 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.