Role for α-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies

R. Mark Grady, Robert W. Grange, Kim S. Lau, Margaret M. Maimone, Mia C. Nichol, James T. Stull, Joshua R. Sanes

Research output: Contribution to journalArticle

262 Scopus citations

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 α-dystrobrevin, a cytoplasmic protein of the DGC, exhibit skeletal and cardiac myopathies. Analysis of double and triple mutants indicates that α-dystrobrevin acts largely through the DGC. Structural components of the DGC are retained in the absence of α-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 α-dystrobrevin in the former.

Original languageEnglish (US)
Pages (from-to)215-220
Number of pages6
JournalNature cell biology
Volume1
Issue number4
DOIs
StatePublished - Aug 1999

ASJC Scopus subject areas

  • Cell Biology

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    Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., & Sanes, J. R. (1999). Role for α-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nature cell biology, 1(4), 215-220. https://doi.org/10.1038/12034