Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance - Université d'Angers Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2008

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

Gavin Hudson
  • Fonction : Auteur
Emma Blakely
  • Fonction : Auteur
Joanna D. Stewart
  • Fonction : Auteur
Langping He
  • Fonction : Auteur
Andrew Schaefer
  • Fonction : Auteur
Philip G. Griffiths
  • Fonction : Auteur
Kati Ahlqvist
  • Fonction : Auteur
Anu Suomalainen
  • Fonction : Auteur
Pascal Reynier
  • Fonction : Auteur
  • PersonId : 991986
Robert Mcfarland
  • Fonction : Auteur
Douglass M. Turnbull
  • Fonction : Auteur
Patrick Chinnery
  • Fonction : Auteur
Robert W. Taylor
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-03419033 , version 1 (08-11-2021)

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Citer

Gavin Hudson, Patrizia Amati-Bonneau, Emma Blakely, Joanna D. Stewart, Langping He, et al.. Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance. Brain - A Journal of Neurology , 2008, 131 (2), pp.329 - 337. ⟨10.1093/brain/awm272⟩. ⟨hal-03419033⟩

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