Rafael Garesse, Carmen Ayuso, Bernd Wissinger, Katell Beauvais, Luisa Iommarini, Joaquiotan Arenas, Dominique Figarella-Branger, Yolanda Campos, Valerio Carelli, Chiara La Morgia, Miguel A. Martín, Alain Furby, Michela Rugolo, Andrea Cossarizza, Claudia Zanna, Pascal Reynier, Pascale Marcorelles, Maria Liguori, Henry Rivera, Jesús González de la Aleja, Pasquale Montagna, María Esther Gallardo, Guy Lenaers, Robert Schwarzenbacher, Rosanna Carroccia, Patrizia Amati-Bonneau, Franck Letournel, Dominique Bonneau, Rocco Liguori, Belén Bornstein, Anne Boissiere, Maria Lucia Valentino, Christophe Verny, Pierre Labauge, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Scienze Neurologiche, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Departamento de Bioquimica Instituto de Investigaciones Biomedicas, Universidad Autonoma de Madrid (UAM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro de Investogacion, Hospital Universitario 12 de Octubre [Madrid], Service de Neurologie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service d'Anatomie Pathologique et Neuropathologique, CHU Marseille, Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU de Saint-Brieuc, Laboratoire de Neurobiologie et Neuropathologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), Institute of Neurological Sciences, National Research Council [Italy] (CNR), Dipartimento di Biologia Evoluzionistica Sperimentale, Dipartimento di Scienze Biomediche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Molecular Genetics Laboratory, University Eye Hospital Tuebingen, Service de neurologie [Angers], Structural Biology, University of Sulzburg, Servicio de genetica, Fundacion Jimenez Diaz [Madrid] (FJD), Hamel, Christian, Universidad Autónoma de Madrid (UAM), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Amati-Bonneau P., Valentino M.L., Reynier P., Gallardo M.E., Bornstein B., Boissiere A., Campos Y, Rivera H, de la Aleja J.G., Carroccia R., Iommarini L., Labauge P., Figarella-Branger D., Marcorelles P., Furby A., Beauvais K., Letournel F., Liguori R., La Morgia C., Montagna P., Liguori M., Zanna C., Rugolo M., Cossarizza A., Wissinger B., Verny C., Schwarzenbacher R., Martin M.A., Arenas J., Ayuso C., Garesse R., Lenaers G., Bonneau D., and Carelli V.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.-- et al., 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. © 2007 The Author(s)., This study has been supported by Telethon-Italy (grant#GGP06233 to V.C.), fondazione Gino Galletti (grant to V.C.), and progetto di ricerca sanitaria finalizzata (grant to V.C. and M.R.). P.A.B., P.R., D.B., A.B. and G.L. were supported by INSERM, the University Hospital of Angers (PHRC 04-12), the University of Angers and Montpellier I and II, France and by grants from Retina France and ‘Ouvrir les yeux’ patients Association. Further financial support comes from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI060205 to B.B. and PI060547 to M.A.M.) and Ministerio de Educación y Ciencia, Spain (BFU2004-04591 to R.G.). Funding to pay the Open Access publication charges for this article was provided by the RFO University of Bologna 2006 grant.