The long-term goals of this project are to understand the molecular basis for the myotubular/centronuclear myopathies and their defects in muscle function, and to use this information to developtherapies for patients with these neuromuscular diseases. X-linked myotubular myopathy (XLMTM) iscaused by mutations of myotubularin (MTM1), the prototypic member of a novel family of lipid phosphatasesthat includes both catalytically active, and inactive (adaptor) family members (myotubularin-related proteinsor 'MTMRs'). There is strong evidence that, despite having similar biochemical activities, differentmyotubularin family members play physiologically distinct roles. For example, mutations of two relatedgenes (MTMR2 and MTMR13) both cause forms of the inherited neuropathy, Charcot-Marie-Tooth (CMT)disease. The primary goals of this Project are 1) to develop and exploit a vertebrate model system(zebrafish) to determine the physiological function(s), of MTM1 and several of it's family members, 2) toutilize candidate gene mutation studies to identify genes for related forms of centronuclear myopathy and 3)to utilize a mouse Mtm1 knockout model of X-linked myotubular myopathy to develop AAV8-mediated genetherapy approaches to treat this fatal disease. Information resulting from the zebrafish studies will allow usto determine the degree of potential functional redundancy between family members and to identify thespecific protein domains responsible for any tissue or molecular specificity. Identification of thesefunctionally complementary MTMR genes may identify appropriate candidate genes to aid in finding thegene(s) for a severe autosomal recessive form of centronuclear myopathy. Observations on recovery fromtransient transcriptional knockdowns of MTM1 in the fish, will also be important in design of effectivetherapies using the mouse model. Gene replacement therapy experiments will address questions of efficacyand the appropriate therapeutic window for this approach to treating XLMTM, and will set the stage forpossible future human clinical trials and animal studies that may attempt treatment via up-regulation offunctionally equivalent MTMRs identified through the zebrafish experiments. Overall, success in this projectwill lead to 1) new insights into the similarities and differences in function between myotubularin and some ofit's related family members, 2) an increased understanding of the molecular pathophysiology underlyingmyotubular myopathy in human patients, and 3) the first indications as to whether a gene therapy approachis likely to be effective in treating this devastating childhood disease.
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