Dystrophin is a large molecular weight component of the muscle and nerve cell cytoskeleton. Disruption of normal function leads to the genetic disorders Duchenne and Becker muscular dystrophy. Deletion mutations are the most common means to disrupt function but other mutations are known to exist. The proposed characterization of these other mutations will greatly increase the accuracy of diagnosis for at risk individuals and should shed additional light on how normal function can be affected. Dystrophin has been shown to be a member of a family of related proteins with overlapping yet discreet functions. Some of these related proteins may partially compensate for absent dystrophin and hence represent potential candidates for therapeutic intervention to strengthen the compensatory ability. These related proteins are themselves prime candidates to be disrupted in other neuromuscular diseases which, like Duchenne and Becker dystrophy, are slowly progressive. New members of the family will be cloned, mapped to chromosomal locations, and tested for disruption in candidate neuromuscular diseases. Functional analysis of these proteins should shed light on their role in the membrane cytoskeleton and how this role is altered in disease. This should result not only in the identification of other disease causing genes, but also proteins with the potential to mitigate the absence of dystrophin in Duchenne dystrophy.
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