title: A unifying genetic model for facioscapulohumeral muscular dystrophy.
abstract: 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.
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
authors: Richard J L F
authors: RJ
authors: Lemmers
authors: Patrick J
authors: PJ
authors: van der Vliet
authors: Rinse
authors: R
authors: Klooster
authors: Sabrina
authors: S
authors: Sacconi
authors: Pilar
authors: P
authors: Camaño
authors: Johannes G
authors: JG
authors: Dauwerse
authors: Lauren
authors: L
authors: Snider
authors: Kirsten R
authors: KR
authors: Straasheijm
authors: Gert Jan
authors: GJ
authors: van Ommen
authors: George W
authors: GW
authors: Padberg
authors: Daniel G
authors: DG
authors: Miller
authors: Stephen J
authors: SJ
authors: Tapscott
authors: Rabi
authors: R
authors: Tawil
authors: Rune R
authors: RR
authors: Frants
authors: Silvère M
authors: SM
authors: van der Maarel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D002675:Child, Preschool; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D026723:Polyadenylation; D020641:Polymorphism, Single Nucleotide; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D014158:Transcription, Genetic; D014162:Transfection; D055815:Young Adult
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D012333:RNA, Messenger