Review Mitochondrial dysfunction and pathophysiology of Charcot–Marie–Tooth disease involving GDAP1 mutations Julien Cassereau a,b,c , Arnaud Chevrollier a,d , Naïg Gueguen a,d , Valérie Desquiret d , Christophe Verny b,c , Guillaume Nicolas b,c , Frédéric Dubas b,c , Patrizia Amati-Bonneau a,d , Pascal Reynier a,c,d , Dominique Bonneau a,c,d , Vincent Procaccio a,c,d, ⁎ a UMR INSERM, U771-CNRS6214, F-49933 Angers, France b University Hospital of Angers, Department of Neurology, Angers, F-49933, France c University of Angers, School of Medicine, Angers, F-49933, France d University Hospital of Angers, Department of Biochemistry and Genetics, Angers, F-49933, France abstract article info Article history: Received 18 June 2010 Revised 2 September 2010 Accepted 4 September 2010 Available online 21 September 2010 Keywords: Charcot–Marie–Tooth GDAP1 Mitochondria Mitochondrial fission Complex I Charcot–Marie–Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair- bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics. © 2010 Elsevier Inc. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 GDAP1: gene and protein (Fig. 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Spectrum of GDAP1 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Phenotypic presentations of CMT disease involving GDAP1 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Electrophysiological and histological aspects of CMT disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Mitochondrial dysfunction and pathophysiology of CMT disorders involving GDAP1 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Role of GDAP1 in mitochondrial dynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Defective mitochondrial bioenergetics associated with GDAP1 mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 Experimental Neurology 227 (2011) 31–41 ⁎ Corresponding author. Biochemistry and Genetics Laboratory, National Centre for Neurodegenerative and Mitochondrial diseases, CHU Angers, 4 rue Larrey, 49933 Angers, France. Fax: +33 2 41 35 40 17. E-mail address: ViProcaccio@chu-angers.fr (V. Procaccio). 0014-4886/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2010.09.006 Contents lists available at ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr