FSHD: a disorder of muscle gene derepression.

Facioscapulohumeral muscular dystrophy (FSHD), the third most common myopathy, is an autosomal dominant disease with an insidious onset and progression. Almost all FSHD patients carry deletions of an integral number of tandem 3.3 kb repeats, termed D4Z4, located on chromosome 4q35. In FSHD patients a deletion of the integral number of D4Z4 repeats generates a fragment that is usually smaller than 35 kb (fewer than 11 repeats), whereas in normal controls the size usually ranges from 50 to 300 kb (between 11 and 150 units). D4Z4 is a repetitive element with heterochromatic features. Recently, 4q35 genes located upstream of D4Z4 have been found to be inappropriately overexpressed specifically in FSHD muscle. An element within D4Z4 has been shown to behave as a silencer that provides a binding site for a transcriptional repressing complex. These results suggest a model in which deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease.