Facioscapulohumeral dystrophy: the path to consensus on pathophysiology

Abstract

Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.

Keywords: DUX4; Epigenetic; Facioscapulohumeral muscular dystrophy; SMCHD1; Tandem repeat sequences.

Figure 1

Schematic of D4Z4 locus on chromosome 4. The D4Z4 locus is in the sub-telomeric region of 4q. The figure shows a three repeat D4Z4 array. CEN indicates the centromeric end and TEL indicates the telomeric end. The DUX4 gene is shown as a gray rectangle with exon 1 and exon 2 in each repeat and exon 3 in the pLAM region telomeric to the last partial repeat (numbered 1, 2, and 3). PAS indicates the polyadenylation site on the permissive 4qA allele that is not present on the non-permissive 4qB allele or on chromosome 10. The arrowed lines represent: Blue, DBE-T transcripts (2.4, 4.4, and 9.8 kb) found in FSHD cells and reported to de-repress DUX4 expression [60]; Black and red, transcripts in the sense and anti-sense direction were detected in both FSHD and control cells [29] and might originate from the mapped sense promoters (black) [29,30] and anti-sense promoters (red) [59] with dashed lines indicating areas that might be degraded or produce si-like small RNAs. NDE, non-deleted element identified as the transcription start site for the DBE-T transcripts [60].

Figure 2

Schematic of novel transcription start sites regulated by DUX4. Upper panel shows the standard transcriptional start site for HEY1 and its intron-exon structure in green. The lower panel shows the transcript induced by DUX4 that originates in a retrotransposon LTR (blue) and splices into novel exons (uncolored) and the annotated HEY1 exons (green) to produce a predicted protein similar to HEY1.