The molecular mechanism of facioscapulohumeral muscular dystrophy (FSHD)

Normally, the 4q chromosome contains 11 to 150 D4Z4 repeats and is highly methylated. In this setting, the DUX4 locus is silent. In FSHD1, there is a contraction of D4Z4 repeats, and in the presence of an A allele, DUX4 is transcribed. In FSHD2, there is hypomethylation of the D4Z4 repeats due to a mutation in SMCHD1, and in the presence of the A allele on chromosome 4, DUX4 is similarly transcribed. DUX4 is a transcription factor that turns on a host of genes, and DUX4 along with the protein products of its target genes are thought to be responsible for muscle pathology.