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

Lookup NU author(s): Professor Gavin Hudson, Joanna Stewart, Emeritus Professor Mike Sir Michael Rawlins, Dr Andrew Schaefer, Philip Griffiths, Professor Bobby McFarlandORCiD, Emeritus Professor Doug Turnbull, Professor Patrick Chinnery, Professor Robert Taylor



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 - polγ, 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. © 2007 The Author(s).

Publication metadata

Author(s): Hudson G, Amati-Bonneau P, Blakely E, Stewart J, He L, Schaefer A, Griffiths P, Ahlqvist K, Suomalainen A, Reynier P, McFarland R, Turnbull D, Chinnery P, Taylor R

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2008

Volume: 131

Issue: 2

Pages: 329-337

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awm272

PubMed id: 18065439


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Funder referenceFunder name
Wellcome Trust
074454Wellcome Trust
G108/539Medical Research Council
G0601943Medical Research Council