Role for alpha-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies.
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.
Pubmed ID: 10559919 RIS Download
Animals | Dystrophin | Dystrophin-Associated Proteins | Genotype | Mice | Mice, Inbred C57BL | Mice, Inbred mdx | Mice, Knockout | Models, Biological | Muscle, Skeletal | Muscular Dystrophy, Animal | Mutation | Neuropeptides | Phenotype | Signal Transduction