This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. X-linked myotubular myopathy is a severe neonatal disorder in which muscle development/maturation is compromised. Mutations in the myotubularin gene (MTM1) located on chromosome Xq28 are causative for this disorder. MTM1 encodes a protein tyrosine phosphatase-like enzyme (PTP) and as a postdoctoral fellow, I made the surprising discovery that it functions to regulate levels of a membrane signaling lipid, phosphatidylinositol 3-phosphate, rather than phosphoprotein substrate(s) as had previously been thought. The myotubularin-related (MTMR) family of phosphoinositide phosphatases represents the largest subfamily of PTPs, with 8 enzymatically active, and 6 catalytically inactive forms. Mutations in two additional MTMR genes, MTMR2 (active) and MTMR13 (inactive), are both associated with type 4B Charcot-Marie-Tooth disease (CMT), an autosomal recessive demyelinating neuropathy. Genetic and biochemical studies suggest that the normal function of MTMRs requires an active/inactive MTMR complex. However, there is little understanding of how each partner in these live/dead MTMR complexes contributes to physiologic function.
This specific aims outlined in this proposal will focus on clarifying the role(s) of live/dead MTMRs in regulating cellular phosphoinositide signaling and how this relates to human neuromuscular disease. We will also determine the mechanisms by which myotubularin function is regulated by protein interactions and post-translational modification as a basis for understanding the signaling pathway(s) it controls during muscle development.
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