西亚试剂：A Unifying Genetic Model for Facioscapulohumeral Muscular D

A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy
Richard J. L. F. Lemmers,1 Patrick J. van der Vliet,1 Rinse Klooster,1 Sabrina Sacconi,2 Pilar Cama?o,3,4 Johannes G. Dauwerse,1 Lauren Snider,5 Kirsten R. Straasheijm,1 Gert Jan van Ommen,1 George W. Padberg,6 Daniel G. Miller,7 Stephen J. Tapscott,5 Rabi Tawil,8 Rune R. Frants,1 Silvère M. van der Maarel1,*

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 (SNPs) 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.

1 Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
2 Centre de reference pour les maladies Neuromusculaires and CNRS UMR6543, Nice University, 06202 Nice, France.
3 Department of Neurosciences, BioDonostia Health Research Institute, Hospital Donostia, 20014 San Sebastián, Spain.
4 CIBERNED, Instituto de Salud Carlos III, 28029 Madrid, Spain.
5 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
6 Department of Neurology, Radboud University Medical Center Nijmegen, 6500 HC Nijmegen, Netherlands.
7 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
8 Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.

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