Document Detail

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD.
MedLine Citation:
PMID:  19728363     Owner:  NLM     Status:  MEDLINE    
Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date, however, the methylation status of contracted repeats on nonpathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a nonpathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In 15 FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD: (1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere.
Jessica C de Greef; Richard J L F Lemmers; Baziel G M van Engelen; Sabrina Sacconi; Shannon L Venance; Rune R Frants; Rabi Tawil; Silvère M van der Maarel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Human mutation     Volume:  30     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-05     Completed Date:  2009-12-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1449-59     Citation Subset:  IM    
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
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MeSH Terms
Chromosomes, Human, Pair 4
DNA Methylation
Epigenesis, Genetic*
Muscle Contraction / genetics*
Muscular Dystrophy, Facioscapulohumeral / genetics*,  physiopathology
Comment In:
Hum Mutat. 2009 Oct;30(10):v   [PMID:  19787630 ]

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