DEFICIENCY OF DYSTROPHIN-ASSOCIATED PROTEINS IN DUCHENNE MUSCULAR-DYSTROPHY PATIENTS LACKING COOH-TERMINAL DOMAINS OF DYSTROPHIN

Dystrophin, the protein product of the Duchenne muscular dystrophy (DM D) gene, is a cytoskeletal protein tightly associated with a large oli gomeric complex of sarcolemmal glycoproteins including dystroglycan, w hich provides a linkage to the extracellular matrix component, laminin . In DMD, the absence of dystrophin leads to a drastic reduction in al l of the dystrophin-associated proteins, causing the disruption of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix which, in turn, may render muscle cells susceptible to necrosi s. The COOH-terminal domains (cysteine-rich and carboxyl-terminal) of dystrophin have been suggested to interact with the sarcolemmal glycop rotein complex. However, truncated dystrophin lacking these domains wa s reported to be localized to the sarcolemma in four DMD patients rece ntly. Here we report that all of the dystrophin-associated proteins ar e drastically reduced in the sarcolemma of three DMD patients in whom dystrophin lacking the COOH-terminal domains was properly localized to the sarcolemma. Our results indicate that the COOH-terminal domains o f dystrophin are required for the proper interaction of dystrophin wit h the dystrophin-associated proteins and also support our hypothesis t hat the loss of the dystrophin-associated proteins in the sarcolemma l eads to severe muscular dystrophy even when truncated dystrophin is pr esent in the subsarcolemmal cytoskeleton.