Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease
Abstract
Objective:
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).
Methods:
A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function.
Results:
Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme.
Conclusions:
We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.
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Supplementary Material
AUTHOR AFFILIATIONS
From the MRC Centre for Neuromuscular Diseases (R.D.S.P., S.M.M., E.C., J.L.H., M.P.L., S.R., M.M.R., M.G.H.) and Department of Clinical Neurophysiology (J.B.), UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK; Neurometabolic Unit (A.C., I.H., S.H., J.L.) and Neurogenetics Unit (M.G.S., C.W., E.E.M.), National Hospital for Neurology and Neurosurgery, London, UK; Department of Molecular Neuroscience (J.L.H., H.H., M.P.L., M.M.R., M.G.H.), UCL Institute of Neurology, London, UK; Department of Clinical Neurophysiology (J.B.), Norfolk and Norwich University Hospital, Norwich, UK; Department of Inherited Metabolic Disease (M.C.), Evelina Children's Hospital, St Thomas' Hospital, London, UK; Clinical Genetics Department (F.F.), Guy's & St Thomas' NHS Foundation Trust, London, UK; Dubowitz Neuromuscular Centre (S.A.R.), UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, UK; Dorset Epilepsy Service (R.P.), Poole Hospital NHS Foundation Trust, Poole, Dorset, UK; Department of Neurology (M.R.), King's College Hospital NHS Foundation Trust, London, UK; Department of Clinical Neurology (J.P.), University of Oxford, John Radcliffe Hospital, Oxford, UK; Division of Clinical Genetics (C.C.), MetroHealth Medical Center, Cleveland, OH; Ferguson Smith Centre for Clinical Genetics (C.L.), Yorkhill Hospital, Glasgow, UK; and Mitochondrial Research Group (S.R.), Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, UK.
STUDY FUNDING
Supported by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre and undertaken at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme.
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Information & Authors
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Copyright © 2012 by AAN Enterprises, Inc.
Publication History
Received: February 16, 2012
Accepted: April 19, 2012
Published online: August 29, 2012
Published in print: September 11, 2012
Disclosure
R.D.S. Pitceathly is funded by MRC grant G0800674. S.M. Murphy is supported by NINDS/ORD (1U54NS065712–01). E. Cottenie is funded by MRC Centre grant G0601943. A. Chalasani, M.G. Sweeney, C. Woodward, E.E. Mudanohwo, I. Hargreaves, S. Heales, and J. Land work at University College London Hospitals/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. J.L. Holton is supported by The Myositis Support Group and the Reta Lila Weston Institute for Neurological Studies. H. Houlden is supported by the MRC and Wellcome Trust. J. Blake, M. Champion, F. Flinter, S. Robb, R. Page, M. Rose, J. Palace, C. Crowe, and C. Longman report no disclosures. M. P. Lunn is supported by MRC Centre grant G0601943. S. Rahman is supported by Great Ormond Street Hospital Children's Charity. M.M. Reilly is supported by MRC Centre grant G0601943, the Muscular Dystrophy Campaign, and NINDS/ORD (1U54NS065712–01). M.G. Hanna is supported by an MRC Centre grant G0601943 and by The Myositis Support Group. Go to Neurology.org for full disclosures.
Authors
Author Contributions
Robert D.S. Pitceathly: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, acquisition of data. Sinéad M. Murphy: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, acquisition of data. Ellen Cottenie: analysis or interpretation of data, acquisition of data. Annapurna Chalasani: analysis or interpretation of data, acquisition of data. Mary G. Sweeney: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data. Cathy Woodward: analysis or interpretation of data, acquisition of data. Ese E. Mudanohwo: analysis or interpretation of data, acquisition of data. Iain Hargreaves: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data, acquisition of data. Simon Heales: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data. John Land: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data. Janice L. Holton: analysis or interpretation of data, acquisition of data. Henry Houlden: drafting/revising manuscript for content, including medical writing for content, analysis or interpretation of data, study supervision or coordination. Julian Blake: analysis or interpretation of data, acquisition of data. Michael Champion: analysis or interpretation of data, acquisition of data. Frances Flinter: analysis or interpretation of data, acquisition of data. Stephanie Robb: analysis or interpretation of data, acquisition of data. Rupert Page: analysis or interpretation of data, acquisition of data. Michael Rose: analysis or interpretation of data, acquisition of data. Jacqueline Palace: analysis or interpretation of data, acquisition of data. Carol Crowe: analysis or interpretation of data, acquisition of data. Cheryl Longman: analysis or interpretation of data, acquisition of data. Michael P. Lunn: drafting/revising manuscript for content, including medical writing for content, acquisition of data. Shamima Rahman: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination. Mary M. Reilly: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination. Michael G. Hanna: drafting/revising manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination.
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