Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy

Abstract

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.Methods We 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.

Homozygous p.V116* mutation inC12orf65results in Leigh syndrome

“…This is consistent with the concept that the extent of the truncation correlates with disease severity. The identical p.V116* homozygous mutation was previously reported in CMT type 6 by Tucci et al (figure 1C) 14. Interestingly, the patients with CMT type 6 and the presently affected twins have Indian ancestry; thus, there is a possibility that the p.V116* mutation might originate from the same founder.…”

A novel mutation in PRPS1 causes X‐linked Charcot‐Marie‐Tooth disease‐5

“…The clinical phenotype and disease progression vary . In addition to time‐course‐dependent neuropathies, there are several types of CMT with additional phenotypic features, such as leucoencephalopathy in CMTX1 with GJB1 mutations, focal segmental glomerulosclerosis in dominant‐inherited intermediate CMT with INF2 mutations, and optic atrophy in CMT with C12orf65 mutations …”

Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction

“… 2 While C12orf65 defects exhibit a wide spectrum of phenotypes, the 3 primary clinical features are optic atrophy, peripheral neuropathy, and spastic paraparesis. 3 Although biochemical studies suggest that these C12orf65 mutations cause mitochondrial dysfunction, 1 , 2 , 4 very few pathologic analyses and no autopsy cases supporting these findings have been reported. In this article, we report an autopsy case associated with 2-nucleotide deletion in the C12orf65 gene.…”