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A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

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Science  24 Sep 2010:
Vol. 329, Issue 5999, pp. 1650-1653
DOI: 10.1126/science.1189044

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Addition by Contraction

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary neuromuscular disorders in Western populations, affecting about 1 in 20,000 people. In most patients, the disorder is associated with contraction of a D4Z4 microsatellite repeat array on chromosome 4q, but this contraction can also occur in the absence of disease, so the underlying genetic mechanisms have remained elusive. Lemmers et al. (p. 1650, published online 19 August; see the Perspective by Mahadevan) now show that FSHD patients carry sequence variants that create a canonical polyadenylation signal for transcripts derived from DUX4, a homeobox gene straddling the last D4Z4 repeat unit and the adjacent sequence. Addition of poly(A) stabilizes the DUX4 transcript, which is likely to be a contributing factor in the disease.