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Handb Clin Neurol. 2011;101:135-42. doi: 10.1016/B978-0-08-045031-5.00010-4.

Caveolinopathies: translational implications of caveolin-3 in skeletal and cardiac muscle disorders.

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1
Unit of Muscular and Neurodegenerative Diseases, G. Gaslini Institute, Genova, Italy.

Abstract

Caveolae are specialized lipid rafts localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae contribute to the maintenance of plasma membrane integrity, constitute specific macromolecular complexes that provide highly localized regulation of ion channels, and regulate vesicular trafficking and signal transduction. In skeletal muscle, the main structural assembly of caveolae is mediated by caveolin-3. Another family of adapter proteins, the cavins, is involved in the regulation of caveolae function and in the trafficking of caveolin-derived structures. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb-girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Many patients show an overlap of these symptoms, and the same mutation can be linked to different clinical phenotypes. An ever-growing interest is also focused on the association between caveolin-3 mutations and heart disorders. Indeed, caveolin-3 mutants have been described in a patient with hypertrophic cardiomyopathy and two patients with dilated cardiomyopathy, and mutations in the caveolin-3 gene (CAV3) have been identified in patients affected by congenital long QT syndrome. Although caveolin-3 deficiency represents the primary event, multiple secondary molecular mechanisms lead to muscle tissue damage. Among these, sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network, and disruption of distinct cell signaling pathways have been determined.

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