Journal
SCIENCE
Volume 329, Issue 5999, Pages 1650-1653Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1189044
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Funding
- Fields Center for FSHD and Neuromuscular Research
- Netherlands Organization for Scientific Research [NWO 917.56.338]
- Netherlands Genomics Initiative [NWO 93.51.8001]
- National Institutes of Health [P01NS069539]
- Muscular Dystrophy Association
- Shaw Family Foundation
- FSH Society
- Dutch FSHD Foundation
- Pacific Northwest Friends of FSH Research
- Centro Investigacion Biomedica en Red para Enfermedades Neurodegenerativas (CIBERNED)
- Basque Government [2008111011]
- Instituto Carlos III, ILUNDAIN Fundazioa
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Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain permissive chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.
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