Résumé :
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Charcot-Marie-Tooth (CMT) disorders are a clinically and genetically heterogeneous group of hereditary neuropathies characterized by chronic distalweakness and sensory loss. CMT4H is an autosomal recessive demyelinating subtype recently mapped by us at chromosome 12p11.21-q13.11, in two consanguineous families of Mediterranean origin. In both families, we identified mutations in FGD4, encoding FGD4/FRABIN, a Rho GDP/GTP Exchange Factor (Rho GEF) specific to RhoGTPase Cdc42. Both mutations affect the same codon: the p.Met298fsX8 (c.893T>G) in the Lebanese and the p.Met298Thr (c.893T>C) in the Algerians.When overexpressing wild-type and truncated (p.Met298fsX8) forms of Frabin in rat primary motoneurons and rat RT4 Schwannomacells, we observed that the truncated form of Frabin induced significantly fewer microspikes than the wild-type. At the transcriptional level, we showed a 60% reduction in FGD4 mRNA levels in Lebanese patient’s fibrobasts, indicating that the truncated mRNA might be degraded by NMD. Moreover, a broad transcriptional study in different human tissues led us to characterize 17 alternative transcripts for FGD4. Interestingly, some of them are deleted of several exons and the corresponding protein lacks one or more functional domains. In consequence, we propose that FRABIN might have different roles in different tissues, depending on the functional domains present on the protein. In conclusion, FRABIN is the first RhoGEF to be identified in CMT disease. Several mechanisms and pathways leading to the pathology remain to be elucidated. However, three main hypothesis might be proposed: 1) loss of Cdc42/Rac1 activation, leading to a disorganization of the cytoskeleton, and perturbation of movements and/or migration 2) disruption of JNK pathway, affecting myelination process 3) implication of FRABIN in the activation of mitochondrial GTPases mutated in CMT (MFN2…), and perturbation of mitochondrial dynamics. We show here some primary results, further experiments are under process in order to validate our hypothesis.
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