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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).
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
URL: http://dx.doi.org/10.1093/brain/awm272
DOI: 10.1093/brain/awm272
PubMed id: 18065439
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