Role for Alpha-Dystrobrevin in the Pathogenesis of Dystrophin-Dependent Muscular Dystrophies

Nat Cell Biol. 1999 Aug;1(4):215-20. doi: 10.1038/12034.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Dystrophin / chemistry
  • Dystrophin / genetics
  • Dystrophin / physiology*
  • Dystrophin-Associated Proteins*
  • Genotype
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Mice, Knockout
  • Models, Biological
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Animal / etiology*
  • Muscular Dystrophy, Animal / genetics
  • Muscular Dystrophy, Animal / physiopathology
  • Mutation
  • Neuropeptides / chemistry
  • Neuropeptides / genetics
  • Neuropeptides / physiology*
  • Phenotype
  • Signal Transduction / physiology

Substances

  • Dystrophin
  • Dystrophin-Associated Proteins
  • Neuropeptides
  • dystrobrevin