The long term goals of this project are to understand the molecular basis for myotubular myopathy (MTM) and its defect in muscle differentiation and to use this information to develop therapies for patients with this neuromuscular disease. X-linked MTM (XLMTM), and its milder variant, centronuclear myopathy (CTNM), are a clinically and genetically heterogeneous group of disorders characterized by congenital skeletal muscle weakness that varies from rapidly fatal in the infantile period (XLMTM) to relatively nonprogressive and compatible with normal life span (CTNM). The unifying features are skeletal muscle weakness and myopathic findings on muscle biopsy, including the presence of undifferentiated-appearing small myofibers with characteristic central nuclei or a central clear zone corresponding to the internuclear space (""""""""myotubes""""""""). XLMTM is caused by mutations of myotubularin, a novel dual specificity protein phosphatase whose role in muscle differentiation is unknown. To better understand myotubularin function and muscle development in general, we propose to 1) characterize SP stem cells in XLMTM muscle, 2) develop gene expression profiles for XLMTM myoblasts and muscle at various stages of differentiation, and 3) use this information to identify and characterize new proteins and pathways involved in muscle differentiation. Comparison of XLMTM-associated changes in gene expression with changes in CTNM and other congenital myopathies and dystrophies will allow identification of disease-specific changes. Correlation with data on various muscular dystrophies studied by other components of this Program Project will allow determination of non-dystrophic and dystrophy-specific pathogenic pathways. Knowledge of XLMTM-specific gene expression abnormalities will help in identifying downstream consequences of myotubularin dysfunction providing potential specific targets for therapeutic interventions to treat this disease. Furthermore, better knowledge of myotubularin's role in muscle differentiation will help in identifying candidate genes for the milder related disease CTNM as well as shed light on normal muscle differentiation.
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