Facioscapulohumeral muscular dystrophy and DUX4: breaking

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHDI has an unusual pathogenic mecha­ nism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chro­ mosome 4q. Recent studies provide compelling evi­ dence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatie tissues. In FSHD, the combination of ineffieient ehromatin sileneing of the D4Z4 repeat and polymorphisms on the FSHD-permis­ sive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease eaused by the inefficient repression of a retrogene in a macrosetellite repeat array.