title: Facioscapulohumeral muscular dystrophy.
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
authors.affiliation: Centre de référence des Maladies Neuromusculaires, Hôpital Archet 1, 151, route de Saint Antoine de Ginestière, 06202 Nice, France; CNRS UMR7277, Inserm U1091, iBV - Institute of Biology Valrose, UNS Université Nice Sophia-Antipolis, Faculté de Médecine, 28 Avenue Valombrose, 06189 Nice Cedex, France. Electronic address: sacconi@unice.fr.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sacconi
authors.affiliation: Clinical Genetics Unit, Dept. of Woman and Child Health, University of Padova, Italy; IRP Città della Speranza, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Centre de référence des Maladies Neuromusculaires, Hôpital Archet 1, 151, route de Saint Antoine de Ginestière, 06202 Nice, France; CNRS UMR7277, Inserm U1091, iBV - Institute of Biology Valrose, UNS Université Nice Sophia-Antipolis, Faculté de Médecine, 28 Avenue Valombrose, 06189 Nice Cedex, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Desnuelle
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D044127:Epigenesis, Genetic; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D056426:Genetic Loci; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009136:Muscular Dystrophies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009154:Mutation; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; C578241:SMCHD1 protein, human
keywords: DNA methylation; DUX4; Epigenetics; Facioscapulohumeral muscular dystrophy; SMCHD1; Subtelomeric repeat