| Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. | |
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MedLine Citation:
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PMID: 23143600 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Richard J L F Lemmers; Rabi Tawil; Lisa M Petek; Judit Balog; Gregory J Block; Gijs W E Santen; Amanda M Amell; Patrick J van der Vliet; Rowida Almomani; Kirsten R Straasheijm; Yvonne D Krom; Rinse Klooster; Yu Sun; Johan T den Dunnen; Quinta Helmer; Colleen M Donlin-Smith; George W Padberg; Baziel G M van Engelen; Jessica C de Greef; Annemieke M Aartsma-Rus; Rune R Frants; Marianne de Visser; Claude Desnuelle; Sabrina Sacconi; Galina N Filippova; Bert Bakker; Michael J Bamshad; Stephen J Tapscott; Daniel G Miller; Silvère M van der Maarel |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-11 |
Journal Detail:
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Title: Nature genetics Volume: 44 ISSN: 1546-1718 ISO Abbreviation: Nat. Genet. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-11-29 Completed Date: 2013-02-13 Revised Date: 2013-04-26 |
Medline Journal Info:
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Nlm Unique ID: 9216904 Medline TA: Nat Genet Country: United States |
Other Details:
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Languages: eng Pagination: 1370-4 Citation Subset: IM |
Affiliation:
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Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Chromosomal Proteins, Non-Histone / genetics* Chromosomes, Human, Pair 18 / genetics CpG Islands / genetics DNA Methylation / genetics Epigenesis, Genetic Female Haplotypes Heredity / genetics* Homeodomain Proteins / genetics* Humans Male Middle Aged Muscular Dystrophy, Facioscapulohumeral / genetics* Mutation* |
| Grant Support | |
ID/Acronym/Agency:
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HG005608/HG/NHGRI NIH HHS; HG006493/HG/NHGRI NIH HHS; P01NS069539/NS/NINDS NIH HHS; R01 AR045203/AR/NIAMS NIH HHS; R01AR045203/AR/NIAMS NIH HHS; UL1 RR024160/RR/NCRR NIH HHS; UL1RR024160/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chromosomal Proteins, Non-Histone; 0/DUX4 protein, human; 0/Homeodomain Proteins; 0/SMCHD1 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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