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Brain Advance Access originally published online on December 24, 2007
Brain 2008 131(2):338-351; doi:10.1093/brain/awm298
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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.

OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes

Patrizia Amati-Bonneau1,2,*, Maria Lucia Valentino3,*, Pascal Reynier1,2, Maria Esther Gallardo4, Belén Bornstein4, Anne Boissière5, Yolanda Campos6, Henry Rivera6, Jesús González de la Aleja6, Rosanna Carroccia3, Luisa Iommarini3, Pierre Labauge7, Dominique Figarella-Branger8, Pascale Marcorelles9, Alain Furby10, Katell Beauvais10, Franck Letournel11, Rocco Liguori3, Chiara La Morgia3, Pasquale Montagna3, Maria Liguori12, Claudia Zanna13, Michela Rugolo13, Andrea Cossarizza14, Bernd Wissinger15, Christophe Verny16, Robert Schwarzenbacher17, Miguel Ángel Martín6, Joaqu{iota}n Arenas6, Carmen Ayuso18, Rafael Garesse4, Guy Lenaers5, Dominique Bonneau1,2 and Valerio Carelli3

1Département de Biochimie et Génétique, Centre Hospitalier Universitaire d’Angers, 2INSERM U694, Angers, France, 3Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy, 4Departamento de Bioquimica Instituto de Investigaciones Biomedicas ‘Alberto Sols’ CSIC-UAM, Facultad de Medicina, Universidad Autonoma de Madrid, CIBERER, ISCIII, Madrid, Spain, 5INSERM U583, Institut des Neurosciences de Montpellier, Universités de Montpellier I et II, Montpellier, France, 6Centro de Investigación, and Servicio de Neurolog{iota}a, Hospital Universitario 12 de Octubre, CIBERER, ISCIII, Madrid, Spain, 7Service de Neurologie, Centre Hospitalier Universitaire de Nîmes, Nîmes, France, 8Service d’Anatomie Pathologique et Neuropathologie, Centre Hospitalier Universitaire—Hopital de la Timone, Marseille, France, 9Service d’Anatomie Pathologique, Centre Hospitalier Universitaire de Brest, Brest, France, 10Service de Neurologie, Centre Hospitalier de Saint-Brieuc, Saint-Brieuc, France, 11Laboratoire de Neurobiologie et Neuropathologie, Centre Hospitalier Universitaire d’Angers, Angers, France, 12Institute of Neurological Sciences, National Research Council - Mangone, Cosenza, Italy, 13Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna, Bologna, Italy, 14Dipartimento di Scienze Biomediche, Sezione di Patologia Generale, Università di Modena e Reggio Emilia, Italy, 15Molecular Genetics Laboratory, University Eye Hospital Tuebingen, Germany, 16Département de Neurologie, Centre Hospitalier Universitaire d’Angers, Angers, France, 17Structural Biology, University of Salzburg, Austria and 18Servicio de Genética. Fundación Jiménez Díaz. CIBERER, ISCIII, Madrid, Spain

Correspondence to: Valerio Carelli, MD, PhD, Laboratorio di Neurogenetica, Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy. E-mail: valerio.carelli{at}unibo.it

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.

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

Abbreviations: BAEPs, brainstem auditory evoked potentials; BDLP, bacterial dynamin-like protein; CT, computerized tomography; CMT, Charcot–Marie-Tooth; COX, cytochrome c oxidase; CPEO, chronic progressive external ophthalmoplegia; DOA, dominant optic atrophy; FBS, fetal bovine serum; LHON, Leber's hereditary optic neuropathy; MEPs, motor evoked potentials; mtDNA, mitochondrial DNA; MRI, magnetic resonance imaging; MRS, MR spectroscopy; nDNA, nuclear DNA; OXPHOS, oxidative phosphorylation; PVEPs, pattern visual evoked potentials; RRFs, Ragged Red Fibres; SDH, succinate dehydrogenase; SEPs, somatosensorial evoked potentials; TP, thymidine phosphorylase

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Received October 1, 2007. Revised November 7, 2007. Accepted November 16, 2007.

*These authors contributed equally to this study.


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