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Hum Mol Genet. 2017 Oct 1;26(19):3736-3748. doi: 10.1093/hmg/ddx258.

Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy.

Raess MA1,2,3,4,5, Cowling BS1,2,3,4, Bertazzi DL5, Kretz C1,2,3,4, Rinaldi B5, Xuereb JM6, Kessler P1,2,3,4, Romero NB7,8,9, Payrastre B6,10, Friant S5, Laporte J1,2,3,4.

Author information

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67404 Illkirch, France.
INSERM U964, 67404 Illkirch, France.
CNRS, UMR7104, 67404 Illkirch, France.
Université de Strasbourg, 67404 Illkirch, France.
Department of Molecular and Cellular Genetics, Université de Strasbourg, CNRS, GMGM UMR7156, 67000 Strasbourg, France.
INSERM U1048 and Université Toulouse 3, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 31432 Toulouse, France.
INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Pitié-Salpêtrière Hospital, Sorbonne Universities, Pierre and Marie Curie University, 75013 Paris, France.
Unit of Neuromuscular Morphology, Institute of Myology.
Reference Center for Neuromuscular Pathology Paris-East, Institute of Myology, Public Hospital Network of Paris, Pitié-Salpêtrière Hospital, 75013 Paris, France.
CHU de Toulouse, Laboratoire d'Hématologie, 31059 Toulouse, France.


Myotubularins (MTMs) 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 MTM1 cause the severe congenital myopathy called myotubular myopathy (or X-linked centronuclear myopathy) while mutations in the MTM1-related protein MTMR2 cause a recessive Charcot-Marie-Tooth peripheral neuropathy. 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 MTMs 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 to MTM1 in yeast and mice. Moreover, adeno-associated virus-mediated exogenous expression of several MTMR2 isoforms ameliorates the myopathic phenotype owing to MTM1 loss, with increased muscle force, reduced myofiber atrophy, and reduction of the intracellular disorganization hallmarks associated with myotubular myopathy. Noteworthy, the short MTMR2 isoform provided a better rescue when compared with the long MTMR2 isoform. In conclusion, these results point to the molecular basis for MTMs 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.

[Indexed for MEDLINE]

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