期刊
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
卷 85, 期 5, 页码 486-492出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jnnp-2013-306387
关键词
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资金
- Wellcome Trust/MRC Joint Call in Neurodegeneration award [WT089698]
- NORD
- Dystonia Medical Research Foundation (DMRF)
- Brain Research Trust (BRT)
- National Institute for Health Research (NIHR) UCLH/UCL Comprehensive Biomedical Research Centre
- MRC through the MRC Sudden Death Brain Bank
- National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
- [G0901254]
- [G0802462]
- MRC [G0701075, G108/638, G0901254, G1001253, MR/J004758/1, G0802760, MC_G1000735, G0802462, MR/K000608/1] Funding Source: UKRI
- Alzheimers Research UK [ARUK-PhD2014-16] Funding Source: researchfish
- Medical Research Council [G0701075, G0901254, MC_G1000735, G0802760, G0802462, MR/K000608/1, G108/638, G1001253, MR/J004758/1] Funding Source: researchfish
- National Institute for Health Research [CL-2013-17-005] Funding Source: researchfish
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.
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