Tucci, A, Liu, Y-T, Preza, E, Pitceathly, RDS, Chalasani, A, Plagnol, V, Land, JM, Trabzuni, D, Ryten, M, Jaunmuktane, Z, Reilly, MM, Brandner, S, Hargreaves, IP, Hardy, J, Singleton, AB, Abramov, AY and Houlden, H (2013) Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy. Journal of Neurology, Neurosurgery and Psychiatry (JNNP), 85 (5). pp. 486-492. ISSN 0022-3050

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Abstract

Objective Charcot-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.
Results We 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.
Conclusions This 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.

Item Type:	Article
Uncontrolled Keywords:	11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Divisions:	Pharmacy & Biomolecular Sciences
Publisher:	BMJ Publishing Group
Related URLs:	Author
Date Deposited:	22 Sep 2020 10:29
Last Modified:	04 Sep 2021 06:39
DOI or ID number:	10.1136/jnnp-2013-306387
URI:	https://researchonline.ljmu.ac.uk/id/eprint/13684

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