CAVEOLIN-3 IN MUSCULAR-DYSTROPHY

The dystrophin-glycoprotein complex (DGC) serves as a link between cyt oplasmic actin, the membrane and the extracellular matrix of striated muscle. Genetic defects in genes encoding a subset of DGC proteins res ult in muscular dystrophy and a secondary decrease in other DGC protei ns. Caveolae are dynamic structures that have been implicated in a num ber of functions including endocytosis, potocytosis and signal transdu ction. Caveolin (VIP-21) is thought to play a structural role in the f ormation of non-clathrin-coated vesicles in a number of different cell types. Caveolin-3, or M-caveolin, was identified as a muscle-specific form of the caveolin family. We show that caveolin-3 co-purifies with dystrophin, and that a fraction of caveolin-3 is a dystrophin-associa ted protein. We isolated the gene for human caveolin-3 and mapped it t o chromosome 3p25. We determined the genomic organization of human cav eolin-3 and devised a screening strategy to look for mutations in cave olin-3 in patients with muscular dystrophy. Of 82 patients screened, t wo nucleotide changes were found that resulted in amino acid substitut ions (G55S and C71W); these changes were not seen in a control populat ion. The amino acid changes map to a functionally important domain in caveolin-3, suggesting that these are not benign polymorphisms and ins tead are disease-causing mutations.