Résumé :
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Communication n° 255. The myotubularin gene family is one of the largest groups within the tyrosine/dual-specificity phosphatase super-family. Among the 14 human members, three are mutated in genetic diseases: X-linked myotubular myopathy (XLMTM, MTM1 gene) and two forms of Charcot-Marie-Tooth neuropathies (CMT, MTMR2 and MTMR13 genes). The myotubularin family encompasses catalytically active and inactive phosphatases, and both classes are mutated in CMT and well conserved from nematode to man. Catalytically active myotubularins dephosphorylate phosphatidylinositol lipids, which are signalling molecules notably involved in membrane trafficking. This activity could be modulated by heterodimerization with catalytically inactive homologues. Our goal is to characterize the physiological myotubularin heterodimers within the myotubularin family. We have investigated the expression level of all mouse MTMR genes during in vitro myoblast differentiation by quantitative PCR and found that levels of MTMR2 and MTMR13 (both mutated in CMT) are stable or decrease, while MTM1, MTMR1, MTMR5, MTMR6 and MTMR12 are upregulated. We have cloned the full open reading frame of all 14 human myotubularins for further study of their respective preferential heterodimerization strength by yeast two hybrid. Production of antibodies against all of them is being started. Partners of MTM1 (mutated in XLMTM), are good candidate genes to be mutated in the autosomal centronuclear myopathies (CNM). CNMs share the central nuclei histology with the neonatal XLMTM form, but display a later onset. We collected 12 dominant families, 10 recessive and 40 sporadic cases. We screened 25 of these patients for mutations in MTMR12/3-PAP, which heterodimerize with MTM1 (Nandurkar et al., PNAS 2003) and is upregulated during in vitro muscle cells differentiation. No variants were found in the entire coding sequence. Other candidate interactors and genes implicated in the myotubularin pathway are currently being sequenced.
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