Genes and Therapies for Centronuclear Myopathies

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DESCRIPTION (provided by applicant): The long-term goals of this project are to understand the molecular basis for a group of closely related congenital myopathies and muscular dystrophies, and to use this information to develop therapies for patients with these debilitating conditions. X-linked myotubular myopathy (XLMTM) is caused by mutations of the MTM1 gene, which encodes myotubularin, an enzyme lipid phosphatase important for biogenesis and function of T tubules, which are the structures in skeletal muscles responsible for transmitting the signal to contract to the contractile apparatus. The centronuclear myopathies (CNMs), of which XLMTM is a subtype, also include forms caused by mutations in the RYR1, DNM2, and BIN1 genes, which are all known or thought to play a role in excitation contraction coupling (ECC) at the triads. Some families with CNM have mutations in genes that have yet to be identified. The specific aims of this proposal are 1) to conduct studies designed to evaluate the potential for myostatin-inhibition therapy in a mouse model of XLMTM and 2) to complete the identification of the various genes that cause human CNMs and related myopathies. Each of the genes shown to cause a form of human CNM will then 3) be modeled in existing or new targeted zebrafish mutants, and 4) these lines will be characterized and developed for use in high throughput drug screens to identify lead compounds with therapeutic potential for these and related disorders of ECC in patients with primary myopathies and muscular dystrophies. The successful conclusion of these studies will result in development of accurate genetic tests to diagnose these conditions in affected children and family members, allowing for reliable family planning to avoid the birth of additional affected children. Furthermore, the identification of new drugs and small molecules that slow or prevent the development of weakness in the mouse and zebrafish models used in this study will set the stage for preclinical testing of new therapies that may one day be used to treat children with these devastating neuromuscular diseases.