title: Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies.
abstract: A dystrophin-containing glycoprotein complex (DGC) links the basal lamina surrounding each muscle fibre to the fibre's cytoskeleton, providing both structural support and a scaffold for signalling molecules. Mutations in genes encoding several DGC components disrupt the complex and lead to muscular dystrophy. Here we show that mice deficient in alpha-dystrobrevin, a cytoplasmic protein of the DGC, exhibit skeletal and cardiac myopathies. Analysis of double and triple mutants indicates that alpha-dystrobrevin acts largely through the DGC. Structural components of the DGC are retained in the absence of alpha-dystrobrevin, but a DGC-associated signalling protein, nitric oxide synthase, is displaced from the membrane and nitric-oxide-mediated signalling is impaired. These results indicate that both signalling and structural functions of the DGC are required for muscle stability, and implicate alpha-dystrobrevin in the former.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA. grady@a1.kids.wustl.edu
authors.forename: R M
authors.initials: RM
authors.lastname: Grady
authors.forename: R W
authors.initials: RW
authors.lastname: Grange
authors.forename: K S
authors.initials: KS
authors.lastname: Lau
authors.forename: M M
authors.initials: MM
authors.lastname: Maimone
authors.forename: M C
authors.initials: MC
authors.lastname: Nichol
authors.forename: J T
authors.initials: JT
authors.lastname: Stull
authors.forename: J R
authors.initials: JR
authors.lastname: Sanes
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D049029:Dystrophin-Associated Proteins; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D009479:Neuropeptides; C098885:dystrobrevin