Facioscapulohumeral muscular dystrophy (FSHD), was one of the first diseases shown to be caused by an unstable repeat in the early 1990s along with spinal and bulbar muscular atrophy (SBMA), myotonic dystrophy (DM1), and fragile X mental retardation (FRAXA), where the latter three are caused by genetically expanding trinucleotide repeats . However, FSHD differs considerably from the trinuclotide repeat diseases, as it is caused by a contraction of a macrosatellite (D4Z4 repeat, 3.3 kb/unit). Moreover, far less is understood about the pathogenic mechanism for FSHD, relative to SBMA, DM1, and FRAXA. This is not due to a shortage of experimental efforts, plausible hypotheses, or collaborative efforts towards understanding FSHD , . The elucidation of FSHD is hampered by the size of the unstable repeat, its sequence complexity, the number of repeat units, and the presence of the repeat on Chromosomes 4 and 10, making analysis technically difficult. The difficulty is compounded further by the absence of an obvious gene, transcript, or protein in the unstable or proximal region; in fact, the D4Z4 repeats have been referred to as “junk” DNA or are thought to be a pseudogene, at best. As a result, FSHD has proved to be one of the most complex and challenging genetic diseases to even a glimpse an underlying pathogenic cause for FSHD. Several recent papers, including one in this issue of PLoS Genetics , have made significant advances that now permit us to expand our understanding of FSHD pathogenesis, a repeat contraction disease.
FSHD presents with weakness of facial muscles, stabilizers of the scapula, or dorsiflexors of the foot. The weakness is progressive with age. Disease severity is highly variable and shows some signs of anticipation, common to other repeat-associated diseases. FSHD is autosomal dominant, characterized by a deletion of D4Z4 repeat units, located in the subtelomere of chromosome 4q35 (Figure 1). Non-affected D4Z4 alleles are polymorphic having 11–100 repeat units; individuals affected with FSHD have 10 or fewer units, but must have at least one unit to show disease, which is now known to be the most telomeric unit. D4Z4 contractions can be inherited or occur as de novo mutations. The contracted D4Z4 repeat arrays show loss of DNA methylation and reduced histone 3 lysine 9 trimethylation, consistent with a more open chromatin structure . The role of the altered chromatin in FSHD pathogenesis is controversial and has been suggested to enhance expression of adjacent genes like FRG1 or ANT1 . More recently, FSHD2-affected individuals that display the altered chromatin but have non-contracted D4Z4 repeats have implicated the derepression of a DUX4 transcript encoded on the D4Z4 repeat units , . However, the mechanism through which the altered chromatin at D4Z4 repeats contributes to FSHD remains unclear.