Common Epigenetic Changes of D4Z4 in Contraction-Dependent and Contraction-Independent FSHD

摘要

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 4qA16l 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 non-pathogenic 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 lOq 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 lOq. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHDL In conclusion, we describe two ways to develop FSHD: (1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere.