Résumé :
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Nonsense-truncating mutations acting by a loss of function mechanism, located in the GDAP1 gene, have been thought to be associated with severe forms of AR-CMT2 disease.The patients harboring nonsense GDAP1 gene mutations usually manifest with first CMT symptoms in early childhood. Some of them have skeletal deformities, additional symptoms (hoarseness) and are wheelchair- bound. In this study, we illustrate the discrepancy between a new missense Gly327Asp GDAP1 gene mutation and an extremely severe phenotype of AR-CMT2 observed in a one CMT family.We characterized the AR-CMT2 phenotype at the clinical, electrophysiological, morphological (sural nerve biopsy), cellular, and genetic level. Given the phenotype-genotype discrepancy observed in our AR-CMT2 family, we decided to analyze the effects of the Gly327Asp mutation at the cellular level.Surprisingly, the Gly327Asp mutation results in the loss of mitochondrial targeting of the GDAP1 protein.Thus, the cellular effect of missense Gly327Asp mutation is identical with molecular damage resulting from nonsense, truncating GDAP1 gene mutations.We conclude that the phenotype of AR-CMT2 (GDAP1) disease should be correlated with cellular effects of GDAP1 gene mutations rather than with previously reported phenotype-genotype correlations.
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