Strukturelle und funktionelle Untersuchungen von Basalmembranen und ihren Rezeptoren in der Pathogenese hereditärer Muskelerkrankungen

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In striated muscle cells the dystrophin-glycoprotein complex (DGC), serves as a link between laminin in the extracellular matrix and the F-actin cytoskeleton. Recent studies extended the numbers of muscular dystrophies associated with primary mutations affecting components of the DGC to six genetically distinct diseases. A key molecule of the complex is the basement membrane receptor dystroglycan, consisting of an extracellular a- and a transmembrane ß-subunit. Dystroglycan has been shown to play an important role in the assembly and formation of basement membranes and in the pathogenesis of DGC associated muscular dystrophies. We identified 4 distinct hereditary muscle diseases with a-dystroglycan deficiency, an altered expression pattern of basement membrane components, and pathology of the extracellular matrix which are different from the known DGC associated muscular dystrophies. The primary genetic defect in none of the 4 diseases has so far been identified. The aim of our project is to further characterize the clinical and biochemical phenotype of the affected patients and to identify their underlying biochemical and genetic defects. Overall the project should contribute to elucidate the role of basement membranes and their receptors in the pathogenesis of hereditary muscle diseases.