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.
Grady
R M
RM
Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110, USA. grady@a1.kids.wustl.edu
Grange
R W
RW
Lau
K S
KS
Maimone
M M
MM
Nichol
M C
MC
Stull
J T
JT
Sanes
J R
JR
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
D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D009479:Neuropeptides; C098885:dystrobrevin