Genomic analysis of facioscapulohumeral muscular dystrophy

The genomic basis of facioscapulohumeral muscular dystrophy (FSHD) is of considerable interest because of the unique nature of the molecular mutation, which is a deletion within a large, complex DNA tandem array (D4Z4). This repeat maps within 30 kb of the 4q telomere. Although D4Z4 repeat units each contain an open reading frame that could encode a homeodomain protein, there is no evidence that the repeat is transcribed, and the underlying disease mechanism probably involves a position effect. A recent study has identified a protein complex bound to D4Z4 that contains YY1 and HMGB2, implicating a role for D4Z4 as a repressor. The 4q telomere has two variants, 4qA and 4qB. Although these alleles are present at almost equal frequencies in the general population, FSHD is associated only with the 4qA allele and never with 4qB. This suggests a functional difference between the telomere variants, either in predisposition to deletions within D4Z4 or in the pathological consequence of the deletion. Comparative mapping studies of the FSHD region in primates, mouse and Fugu rubripes have given insights into the evolutionary history of the D4Z4 repeat and of 4qter, although as yet they have not provided any solutions to the FSHD puzzle.