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- W2754570079 abstract "Myotubularins are active or dead phosphoinositides phosphatases defining a large protein family conserved through evolution and implicated in different neuromuscular diseases. Loss-of-function mutations in myotubularin (MTM1) cause the severe congenital myopathy called myotubular myopathy (or X-linked centronuclear myopathy) while mutations in the myotubularin-related protein MTMR2 cause Charcot-Marie-Tooth peripheral neuropathy (CMT4B1). Here we aimed to determine the functional specificity and redundancy of MTM1 and MTMR2, and to assess their abilities to compensate for a potential therapeutic strategy. Using molecular investigations and heterologous expression of human myotubularins in yeast cells and in Mtm1 knockout mice, we characterized several naturally occurring MTMR2 isoforms with different activities. We identified the N-terminal domain as responsible for functional differences between MTM1 and MTMR2. An N-terminal extension observed in MTMR2 is absent in MTM1, and only the short MTMR2 isoform lacking this N-terminal extension behaved similarly as MTM1 in yeast and mice. Moreover, adeno-associated virus (AAV)-mediated exogenous expression of several MTMR2 isoforms ameliorates the myopathic phenotype due to MTM1 loss, with increased muscle force, reduced myofiber atrophy, and reduction of the intracellular disorganization hallmarks associated to myotubular myopathy. Noteworthy, the short MTMR2 isoform provided a better rescue when compared to the long MTMR2 isoform. In conclusion, these results point to the molecular basis for myotubularins functional specificity. They also provide the proof-of-concept that expression of the neuropathy-associated MTMR2 gene improves the MTM1-associated myopathy, thus identifying MTMR2 as a novel therapeutic target for myotubular myopathy." @default.
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- W2754570079 date "2017-10-01" @default.
- W2754570079 modified "2023-09-27" @default.
- W2754570079 title "Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy" @default.
- W2754570079 doi "https://doi.org/10.1016/j.nmd.2017.06.281" @default.
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