Duchenne and Becker muscular dystrophies are caused by genetic lesions of the dystrophin gene. These mutations result in the production of an abnormal protein or its absence. The long term goal of our research is to fully characterize the function of dystrophin to facilitate early detection, treatment and perhaps prevention of muscular dystrophy. During the last three years, we have identified and characterized a protein module, the WW domain, which binds proline rich ligands. The WW domain is present within the carboxyterminal region of dystrophin. Dystrophin interacts with several proteins including B-dystroglycan, which spans the membrane and communicates with the extracellular matrix. The overall hypothesis to be evaluated is that the WW domain, EF hands and the ZZ domain of dystrophin mediate interaction with B-dystroglycan in vivo, and that without this interaction, a partial or complete dystrophic phenotype results at the level of organism.
Our specific aims are: 1. To characterize the specificity of the interaction between the WW domain of dystrophin and the proline rich core of B-dystroglycan using site directed mutagenesis, phage displayed peptide repertoires, the SPOT technique of peptide synthesis, and immunoprecipitation. 2. To elucidate the role of the cysteine rich region of dystrophin in modulating the interaction between the WW domain, EF hands plus the Z domain of dystrophin and B-dystroglycan by mutational analysis and x-ray crystallography. 3. To provide evidence of the biological role of modular protein domains of dystrophin (the WW domain, EF hands, the Z domain) by showing that dystrophin transgenes in which any of the four domains alone or in combination with other modules is point mutated can only partially complement the mdx phenotype (muscular dystrophy in mice), in contrast to the control, a wild type transgene, which fully complements the mdx phenotype. These studies will provide insight into molecular function of dystrophin and could point towards potential therapies for Duchenne and Becker muscular dystrophies.
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