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Acta Myol. 2009 July; 28(1): 34.
PMCID: PMC2859637

I-2. FSHD clinical manifestations and molecular genetics: an update

Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited dystrophy with a prevalence of 1:20,000 and a distinctive clinical presentation. The genetic defect, a loss of a critical number of a 3.3Kb repetitive element (D4Z4) on the 4q35 subtelomeric region, was described in 1991, yet the causal gene(s) and the molecular mechanism remain elusive. The absence of a mutated gene sequence and the fact that haploinsufficiency of 4q35 does not result in FSHD clearly indicate that FSHD is caused by a deleterious gain of function. Early researchers, failing to convincingly demonstrate the presence of transcribed sequences in vivo from within the D4Z4 repeats, suggested that contractions of D4Z4 repeats resulted in altered transcription of genes centromeric to the repeats. More recent data suggests that FSHD is caused by a more complex and heterogeneous genetic defect than a simple reduction in repeat number and that these changes ultimately result in a more permissive chromatin structure at D4Z4. These chromatin changes have caused researchers to come full circle and reconsider the possibility that transcripts from within D4Z4, in particular the DUX4 gene, play a pathogenic role in FSHD. The DUX4 gene is phylogenetically highly conserved but DUX4 protein can only be demonstrated in stem cells. Moreover, induced expression of DUX4 shows it to be highly toxic to mature cells causing cell death by apoptosis. However, recent findings suggest that partial transcripts may be produced by the DUX4 gene and that these transcripts are less toxic to cells but nevertheless can interfere with normal myogenesis. The implications of these findings on the pathogenesis and treatment of FSHD will be discussed.

Articles from Acta Myologica are provided here courtesy of Pacini Editore