Limb girdle muscular dystrophy type 2B (LGMD 2B) and Miyoshi myopathy (MM) are caused by defects in a gene that encodes a newly identified protein “dysferlin”. The long-term objectives of this proposal are to characterize the biological properties of dysferlin and its role in the pathogenesis of LGMD 2B and MM and to initiate studies of cell therapy in these diseases.

Dr. Brown is trying to characterize the biological properties of dysferlin and its role in the pathogenesis of limb-girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), and to initiate studies of cell therapy in these two diseases. These biological studies will entail an investigation of dysferlin-interacting proteins, using both conventional and newer (microarray) methods. The cell therapy studies will characterize muscle stem cells in dysferlin-deficient mice and assess the feasibility of using normal muscle stem cells to replace dysferlin in these animals.

AIMS:

• To characterize dysferlin gene mutations and abnormalities of dysferlin protein expression in patients with MM and LGMD 2B and use this information to extend our studies of dysferlin as a novel muscle membrane protein.
• To identify proteins that interact with normal and mutant dysferlin via conventional analysis.
• To use chip-based mRNA expression to analyze/compare dysferlin-deficient human muscle to identify changes of muscle gene expression that are either common to all dystrophies or specific to the dysferlinopathies.
• To validate results of expression arrays and characterize genes that are unique to each of the dystrophies as potential modifiers of the phenotype and begin to test new hypotheses about the molecular pathogenesis of muscle degeneration in the dysferlinopathies.
• To analyze SP cell populations in MM and LGMD 2B in a mouse model of dysferlin deficiency.