Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?

Abstract

Facioscapulohumeral muscular dystrophy (FS HD) is the third most common muscular dystrophy after the dystrophinopathies and myotonic dystrophy and is associated with a typical pattern of muscle weakness. Most patients with FSHD carry a large deletion in the polymorphic D4Z4 macrosatellite repeat array at 4q35 and present with 1-10 repeats whereas non-affected individuals possess 11-150 repeats. An almost identical repeat array is present at 10q26 and the high sequence identity between these two arrays can cause difficulties in molecular diagnosis. Each 3.3-kb D4Z4 unit contains a DUX4 (double homeobox 4) gene that, among others, is activated upon contraction of the 4q35 repeat array due to the induction of chromatin remodelling of the 4qter region. A number of 4q subtelomeric sequence variants are now recognised, although FSHD only occurs in association with three 'permissive' haplotypes, each of which is associated with a polyadenylation signal located immediately distal of the last D4Z4 unit. The resulting poly-A tail appears to stabilise DUX4 mRNAs transcribed from this most distal D4Z4 unit in FSHD muscle cells. Synthesis of both the DUX4 transcripts and protein in FSHD muscle cells induces significant cell toxicity. DUX4 is a transcription factor that may target several genes which results in a deregulation cascade which inhibits myogenesis, sensitises cells to oxidative stress and induces muscle atrophy, thus recapitulating many of the key molecular features of FSHD.

Deciphering transcription dysregulation in FSH muscular dystrophy

“…In addition, the levels or timing of inappropriate expression of DUX4-fl in vivo in myogenic precursors (or the extent of dysregulation of downstream genes) may be different than in vitro , just as is the case for the reprogramming factor Zcan4 in embryos vs embryonal stem cells 67,68 (see below). Nonetheless, FSHD muscle appears to have much lower levels of DUX4-fl expression than cultured FSHD myotubes and is sometimes undetectable in affected FSHD muscle biopsies, 42,52,61 a finding that is consistent with the models based upon the central role of myogenic precursor cells in disease pathogenesis.…”

“…However, a major complication in understanding the relationship of DUX4-fl transcripts to FSHD pathogenesis is their extraordinarily low average abundance in FSHD1 and FSHD2 myoblasts, myotubes, and muscle. 52 Detection of DUX4-fl RNA in FSHD biomaterials requires nested PCR 6 or unusually high amounts of cDNA template (400 ng). 5,53 The need for these non-quantitative conditions for RT-PCR raises fundamental questions about the nature of the causal association of DUX4-fl and the disease pathology.…”

Are Antioxidants a Potential Therapy for FSHD? A Review of the Literature

“…As FSHD1 is the most common form of FSHD, the scope of this review is limited to the FSHD1 condition only. FSHD1, which hereafter will be referred to as FSHD, is characterised by a shortened D4Z4 repeat array which consists of 1–10 repeats, whereas in healthy individuals the repeat units range from 11 to 150 [18]. Individuals can present with a similar D4Z4 shortening which is located on chromosome 10q; however, no contractions of the 10qter have been reported to result in FSHD [19, 20].…”

Trypanosoma brucei RAP1 maintains telomere and subtelomere integrity by suppressing TERRA and telomeric RNA:DNA hybrids

“…Subtelomere integrity is also important for human health. Deletion of subtelomeric D4Z4 repeats derepresses a nearby DUX4 gene in muscle cells and leads to facioscapulohumeral muscular dystrophy (4). 5% of unexplained human mental impairment cases are caused by cryptic unbalanced subtelomeric rearrangements (5).…”