Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence

Abstract

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.

Figure 1

Schematic of the FSHD locus. (a) The D4Z4 repeat (triangles) is located in the subtelomere of chromosome 4q and can vary between 11–100 copies in the unaffected population. This repeat structure has a closed chromatin structure characterized by heterochromatic histone modifications (dense springs), high DNA methylation levels (closed circles) and complex bidirectional transcriptional activity (grey arrows). Candidate genes DUX4, FRG2, FRG1 and ANT1 are indicated. (b) In patients with FSHD, the chromatin structure of D4Z4 adopts a more open configuration (open springs and open circles) leading to inefficient transcriptional repression (black arrows) of the D4Z4 repeat. (c) The DUX4 gene is located within each D4Z4 unit. On permissive chromosomes, the last copy of the DUX4 genes splices to a third exon located in the region immediately flanking the repeat and stabilizing the transcript due to the presence of a polyadenylation (polyA) signal. Figure modified, with permission, from [52].

Figure 2

A unifying mechanism for FSHD. Upon (a) contraction of the D4Z4 repeat (FSHD1) or by (b) a yet unknown mechanism (FSHD2), the D4Z4 repeat array (triangles) adopts a more open chromatin configuration (orange > green dots) leading to the leaky expression of DUX4 mRNA. On permissive chromosomes, this mRNA is stabilized due to the presence of a canonical polyadenylation signal immediately distal to the D4Z4 repeat array. (c) Non-permissive chromosomes do not have this polyadenylation signal and therefore DUX4 mRNA gets rapidly degraded. The DUX4 mRNA encodes for a nuclear double homeobox protein that when expressed in muscle induces apoptosis.