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Brain Advance Access originally published online on December 7, 2007
Brain 2008 131(2):329-337; doi:10.1093/brain/awm272
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance

Gavin Hudson1, Patrizia Amati-Bonneau2, Emma L. Blakely1, Joanna D. Stewart1, Langping He1, Andrew M. Schaefer1, Philip G. Griffiths3, Kati Ahlqvist4, Anu Suomalainen4, Pascal Reynier2, Robert McFarland1, Douglass M. Turnbull1,5, Patrick F. Chinnery1,5 and Robert W. Taylor1,5

1Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, UK, 2INSERM U694, Angers and Département de Biochimie et Génétique, Centre Hospitalier Universitaire d’Angers, France, 3Department of Ophthalmology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, UK, 4Research Program of Molecular Neurology, University of Helsinki, and Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland and 5Institute of Human Genetics, Newcastle University, UK

Correspondence to: Prof. Patrick F. Chinnery, Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK E-mail: p.f.chinnery{at}ncl.ac.uk

Mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations in genes encoding one of three well-characterized proteins—pol{gamma}, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX). The disorder presented with visual failure and optic atrophy in childhood, followed by PEO, ataxia, deafness and a sensory-motor neuropathy in adult life. COX-deficient skeletal muscle fibres contained supra-threshold levels of multiple mtDNA deletions, and genetic linkage, sequencing and expression analysis excluded POLG1, PEO1 and SLC25A4, the gene encoding Ant 1, as the cause. This demonstrates the importance of OPA1 in mtDNA maintenance, and implicates OPA1 in diseases associated with secondary defects of mtDNA.

Key Words: mitochondria; mitochondrial DNA; mitochondrial encephalomyopathy; autosomal dominant progressive external ophthalmoplegia; autosomal dominant optic atrophy; multiple mtDNA deletions

Abbreviations: ATP, adenosine triphosphate; COX, cytochrome c oxidase; DGUOK, deoxyguanosine kinase gene; LOD, log of the odds ratio; mtDNA, mitochondrial DNA; PEO, progressive external ophthalmoplegia; pol{gamma}, polymerase gamma; POLG1, polymerase gamma gene

Received October 1, 2007. Revised October 16, 2007. Accepted October 17, 2007.


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