Titre :
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In vivo functional studies and phenotypic correction of myotubular myopathies by gene transfer in mice (poster) : Acte de colloque : 4ème colloque international de Myologie (9-13 mai 2011; Lille (France))
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contenu dans :
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Auteurs :
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Hnia K ;
Cowling B ;
Koebel P ;
Kretz C ;
Mandel JL ;
Laporte J
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Type de document :
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Article
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Editeur :
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AFM-TELETHON, 2011
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Pages :
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p. 62
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Langues:
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Anglais
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Mots-clés :
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colloque
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myopathie myotubulaire liée à l'X
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souris modèle
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Résumé :
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Centronuclear myopathies are rare muscle diseases characterized by muscle weakness associated to the abnormal positioning of nuclei in muscle fibers. Mutations in myotubularin (MTM1) have been identified in the most severe form of CNM: the X-linked CNM (XLCNM) also called myotubular myopathy. Myotubularins (MTMs) define a large family of proteins within the phosphoinositides phosphatase family. Two MTM1 homologues ubiquitously expressed, Myotubularins related-2 (MTMR2) and MTMR13, are mutated in demyelinating Charcot-Marie-Tooth type 4B (CMT4B) peripheral neuropathies, suggesting a common molecular mechanism between these myopathies and neuropathies but different tissue-specificity. To decipher common and specific pathomechanisms, we are modulating the functions of these proteins or proteins domains in mouse skeletal muscles using gene knock-out and adenovirus-associated vectors (AAV) directed transduction. The Mtm1 knock-out mouse model reproduced the histopathological defects typical of XLCNM. Expression of MTM1 using AAV-Mtm1 successfully rescued a nearly normal muscle function in Mtm1 knockout mice. We aim to identify the domain(s) needed for the muscle role of MTM1 by testing the potential of phenotypic rescue with MTM1 mutants and truncated MTM1 constructs using AAV injection in Mtm1 knock-out skeletal muscle. We also aim to characterize tissue-specific interactors of Myotubularins. Recent studies demonstrated the interaction between MTMR2 and a member of DLG (disc large) family, and possible heterodimerization within members of the myotubularin family. We will thus focus on DLG and MTMs in skeletal muscle and test their binding specificities against MTM1 and MTMR2.This project should lead to a better comprehension of myotubularin function and pathway in skeletal muscle.
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