Skip to Main content Skip to Navigation
Journal articles

OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.

Abstract : Mutations in OPA1, a dynamin-related GTPase involved in mitochondrial fusion, cristae organization and control of apoptosis, have been linked to non-syndromic optic neuropathy transmitted as an autosomal-dominant trait (DOA). We here report on eight patients from six independent families showing that mutations in the OPA1 gene can also be responsible for a syndromic form of DOA associated with sensorineural deafness, ataxia, axonal sensory-motor polyneuropathy, chronic progressive external ophthalmoplegia and mitochondrial myopathy with cytochrome c oxidase negative and Ragged Red Fibres. Most remarkably, we demonstrate that these patients all harboured multiple deletions of mitochondrial DNA (mtDNA) in their skeletal muscle, thus revealing an unrecognized role of the OPA1 protein in mtDNA stability. The five OPA1 mutations associated with these DOA 'plus' phenotypes were all mis-sense point mutations affecting highly conserved amino acid positions and the nuclear genes previously known to induce mtDNA multiple deletions such as POLG1, PEO1 (Twinkle) and SLC25A4 (ANT1) were ruled out. Our results show that certain OPA1 mutations exert a dominant negative effect responsible for multi-systemic disease, closely related to classical mitochondrial cytopathies, by a mechanism involving mtDNA instability.
Document type :
Journal articles
Complete list of metadata

Cited literature [49 references]  Display  Hide  Download
Contributor : Christian Hamel <>
Submitted on : Monday, July 7, 2008 - 9:54:22 AM
Last modification on : Monday, February 15, 2021 - 3:00:10 PM
Long-term archiving on: : Friday, May 28, 2010 - 9:30:53 PM


Explicit agreement for this submission




Patrizia Amati-Bonneau, Maria Lucia Valentino, Pascal Reynier, Maria Esther Gallardo, Belén Bornstein, et al.. OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes.. Brain - A Journal of Neurology , Oxford University Press (OUP), 2008, 131 (Pt 2), pp.338-51. ⟨10.1093/brain/awm298⟩. ⟨inserm-00293604⟩



Record views


Files downloads