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Role for α-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 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.

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Figure 1: Model of the DGC in skeletal muscle.
Figure 2: Mutation of the α-dystrobrevin gene.
Figure 3: Histology of adbn–/– muscle.
Figure 4: Skeletal muscle from DGC mutants.
Figure 5: Immunostaining of skeletal muscle from wild-type (WT), adbn–/– and mdx mice with antibodies to DGC-associated proteins.
Figure 6: Immunoblots of skeletal-muscle proteins from wild type (+/+) and adbn–/– (–/–) mice.
Figure 7: cGMP levels in control and mutant muscle.

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Acknowledgements

We thank S. Froehner and M. Peters for antibodies. This work was supported by the NIH and MDA (J.R.S. and R.M.G.).

Correspondence and requests for materials should be addressed to R.M.G.

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Correspondence to R. Mark Grady.

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Grady, R., Grange, R., Lau, K. et al. Role for α-dystrobrevin in the pathogenesis of dystrophin-dependent muscular dystrophies. Nat Cell Biol 1, 215–220 (1999). https://doi.org/10.1038/12034

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