A unifying genetic model for facioscapulohumeral muscular dystrophy.

Publication Type:

Journal Article


Science (New York, N.Y.), Volume 329, Issue 5999, p.1650-3 (2010)


2010, Adolescent, Adult, Aged, Base Sequence, Center-Authored Paper, Child, Preschool, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 4, Female, Genetic Predisposition to Disease, Haplotypes, Homeodomain Proteins, Human Biology Division, Humans, Male, Middle Aged, Models, Genetic, Molecular Sequence Data, Muscular Dystrophy, Facioscapulohumeral, Polyadenylation, Polymorphism, Single Nucleotide, Repetitive Sequences, Nucleic Acid, RNA Stability, RNA, Messenger, Transcription, Genetic, Transfection, Young Adult


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.