A locus-specific database for mutations in GDAP1 allows analysis of genotype-phenotype correlations in Charcot-Marie-Tooth diseases type 4A and 2K

<p>Abstract</p> <p>Background</p> <p>The ganglioside-induced differentiation-associated protein 1 gene (<it>GDAP1</it>), which is involved in the Charcot-Marie-Tooth disease (CMT), the most commonly inherited peripheral neuropathy, encodes a protein anchored to the mitochondrial outer membrane. The phenotypic presentations of patients carrying <it>GDAP1 </it>mutations are heterogeneous, making it difficult to determine genotype-phenotype correlations, since the majority of the mutations have been found in only a few unrelated patients. Locus-specific databases (LSDB) established in the framework of the Human Variome Project provide powerful tools for the investigation of such rare diseases.</p> <p>Methods and Results</p> <p>We report the development of a publicly accessible LSDB for the <it>GDAP1 </it>gene. The <it>GDAP1</it> LSDB has adopted the Leiden Open-source Variation Database (LOVD) software platform. This database, which now contains 57 unique variants reported in 179 cases of CMT, offers a detailed description of the molecular, clinical and electrophysiological data of the patients. The usefulness of the <it>GDAP1 </it>database is illustrated by the finding that <it>GDAP1 </it>mutations lead to primary axonal damage in CMT, with secondary demyelination in the more severe cases of the disease.</p> <p>Conclusion</p> <p>Findings of this nature should lead to a better understanding of the pathophysiology of CMT. Finally, the <it>GDAP1 </it>LSDB, which is part of the mitodyn.org portal of databases of genes incriminated in disorders involving mitochondrial dynamics and bioenergetics, should yield new insights into mitochondrial diseases.</p

Simultaneous MFN2 and GDAP1 mutations cause major mitochondrial defects in a patient with CMT

Mutations in the MFN2 gene are associated with Charcot-Marie-Tooth disease type 2A (CMT2A), a dominant axonal CMT, whereas mutations in GDAP1 are associated with recessive demyelinating CMT (CMT4A), recessive axonal CMT (AR-CMT2), and dominant axonal CMT (CMT2K). Both proteins are involved in energy metabolism and dynamics of the mitochondrial network. We have previously reported that, in fibroblasts from patients with CMT, MFN2 mutations resulted in a mitochondrial energy coupling defect, whereas dominant mutation in GDAP1 resulted in defective complex I activity. In this study, we investigated mitochondrial bioenergetics from a severely affected patient with CMT harboring combined mutations in both GDAP1 and MFN2 genes

PHYSIOPATHOLOGIE DE LA MALADIE DE CHARCOT-MARIE- TOOTH DE TYPE 4A/2K ASSOCIEE AUX MUTATIONS DU GENE GDAP1

Charcot-Marie-Tooth disease represents a large group of heterogeneous disorders leading to inherited peripheral neuropathies. Mutations in GDAP1 (Ganglioside-induced Differentiation-Associated-Protein 1), encoding a protein anchored to the outer mitochondrial membrane, are associated with recessive forms of CMT (CMT4A) and with autosomal dominant forms (CMT2K). The function of the GDAP1 protein is not fully understood but it has been suggested to play a role in mitochondrial fission. The aim of this work was to investigate mitochondrial bioenergetics in skin fibroblasts from patients harboring mutations in GDAP1. We showed a mitochondrial complex I deficiency with a reduction of ATP production, without major alteration of mitochondrial network. This complex I defect was associated with a reactive oxygen species production and a dysregulation of the NAD-dependent deacetylase sirtuin-1 level, a protein involved in mitochondrial biogenesis. These results demonstrate that GDAP1 protein plays a major role in mitochondrial energetic metabolism. In order to establish genotype-phenotype correlations, we have created an international locus specific database containing the sequence variants of GDAP1 associated with patient clinical data.La maladie de Charcot-Marie-Tooth (CMT) représente un large groupe hétérogène de neuropathies périphériques héréditaires. Les mutations du gène GDAP1 (ganglioside-induced differentiation-associated protein 1), codant pour une protéine de la membrane externe mitochondriale, sont associées à des formes récessives (CMT4A) et à des formes dominantes de CMT (CMT2K). GDAP1 participerait au processus de fission des mitochondries sans que son rôle soit bien défini. L'objectif de ce travail a été d'étudier le métabolisme énergétique mitochondrial de cellules de peau issues de patients porteurs de mutations du gène GDAP1. Nous avons mis en évidence un déficit énergétique mitochondrial associé au complexe I sans altération majeure du réseau mitochondrial. Ce déficit fonctionnel du complexe I est associé à une production accrue de radicaux libres et un défaut de régulation de la protéine sirtuine 1, une désacétylase NAD-dépendante impliquée dans la biogenèse mitochondriale. Nos travaux ont ainsi montré que GDAP1 a un rôle important dans le métabolisme énergétique mitochondrial. Dans le but d'établir des corrélations génotype-phénotype, nous avons créé une base de données internationale permettant de répertorier les données cliniques et les variations de séquence de GDAP1

Maladie de charcot-Marie-Tooth de type 4A/2K par mutations du gene GDAP1

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

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