The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle

Dysferlin is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited, forms of muscular dystr ophy designated Miyoshi myopathy (MM) and limb girdle muscular dystrophy ty pe 2B (LGMD2B), respectively. The function of dysferlin is not defined. Cav eolin-3 is another skeletal muscle membrane protein which is important in t he formation of caveolae and whose mutations cause dominantly inherited lim b girdle muscular dystrophy type 1C (LGMD1C). We report that dysferlin co-i mmunoprecipitates with caveolin-3 from biopsied normal human skeletal muscl es. We also describe abnormal localization of dysferlin in muscles from pat ients with LGMD1C including novel missense mutation (T64P) in the human cav eolin-3 gene (CAV3). The immunoprecipitation data are consistent with the p arallel observation that dysferlin immunostaining is not normal in LGMD1C m uscles. Amino acid sequence analysis of the dysferlin protein reveals seven sites that correspond to caveolin-3 scaffold-binding motifs, and one site that is a potential target to bind the WW domain of the caveolin-3 protein. This is the first description of a possible dysferlin interacting protein; it suggests the hypothesis that one function of dysferlin may be to intera ct with caveolin-3 to subserve signaling functions of caveolae.