• Arianna Tucci, Yo-Tsen Liu, Elisabeth Preza, Robert D S Pitceathly, Annapurna Chalasani, Vincent Plagnol, John M Land, Daniah Trabzuni, Mina Ryten, UKBEC, Zane Jaunmuktane, Mary M Reilly, Sebastian Brandner, Iain Hargreaves, John Hardy, Andrew B Singleton, Andrey Y Abramov, and Henry Houlden.
• Department of Molecular Neuroscience and Reta Lila Weston Research Laboratories, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, , London, UK.
• J. Neurol. Neurosurg. Psychiatr. 2014 May 1; 85 (5): 486492486-92.

ObjectiveCharcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified.MethodsWe here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation. Using a variety of methods we investigated the possibility of mitochondrial impairment in the patients cell lines.ResultsWe described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene. We report mitochondrial impairment in the patients cell lines, followed by multiple lines of evidence which include decrease of complex V activity and stability (blue native gel assay), decrease in mitochondrial respiration rate and reduction of mitochondrial membrane potential.ConclusionsThis work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.

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