Exposing a DUX Tale

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Science  24 Sep 2010:
Vol. 329, Issue 5999, pp. 1607-1608
DOI: 10.1126/science.1195984

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Facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, is characterized by progressive weakness that starts in the facial muscles, proceeds to the upper back (scapula) and shoulder-upper arm regions (humeral), and eventually affects the trunk and lower extremities. Since 1992, this disorder has been associated with an array of repeated DNA sequences (called D4Z4) on chromosome 4 (1). An unaffected chromosome 4 has between 11 and more than 100 repeat units within D4Z4, but when this is shortened to 1 to 10 units, disease develops (see the figure). How this contraction leads to disease has been a mystery. Over the past 3 years, analyses of chromosome 4q35 have identified a combination of DNA sequences (haplotype 4A161) associated with susceptibility to FSHD, suggesting that specific sequence variations are coupled to disease pathogenesis in conjunction with D4Z4 contraction (2). On page 1650 of this issue, Lemmers et al. (3) provide an intriguing unifying model for FSHD pathogenesis based on very high resolution haplotype mapping and sequence analyses and careful study of exceptional pedigrees.