OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes
| Autor: | 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 |
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| Přispěvatelé: | 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., Carelli V. |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Male
Models Molecular Mitochondrial encephalomyopathy Ophthalmoplegia Chronic Progressive External MESH: Ophthalmoplegia Chronic Progressive External DNA Mutational Analysis ComputingMilieux_LEGALASPECTSOFCOMPUTING MESH: Base Sequence medicine.disease_cause OPA1 GTP Phosphohydrolases MESH: Magnetic Resonance Imaging 0302 clinical medicine Mitochondrial myopathy MESH: Child MESH: Syndrome MESH: DNA Mutational Analysis Child Genetics MESH: Aged 0303 health sciences Mutation MESH: Muscle Skeletal MESH: Middle Aged Mitochondrial Myopathies Syndrome Middle Aged Magnetic Resonance Imaging Pedigree 3. Good health MESH: Optic Atrophy Autosomal Dominant mitochondrial fusion MESH: Mitochondrial Myopathies Female [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] MESH: Tomography X-Ray Computed MESH: Models Molecular Adult Mitochondrial DNA MESH: GTP Phosphohydrolases MESH: Pedigree Mutation Missense Biology DNA Mitochondrial 03 medical and health sciences Optic Atrophy Autosomal Dominant medicine Humans Point Mutation [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Muscle Skeletal Aged 030304 developmental biology MESH: Point Mutation MESH: Mutation Missense MESH: Humans Base Sequence Point mutation MESH: DNA Mitochondrial MESH: Adult Fibroblasts medicine.disease Molecular biology eye diseases MESH: Male MESH: Fibroblasts Chronic progressive external ophthalmoplegia Dominant optic atrophy Mitochondria mtDNA multiple deletions Neurology (clinical) Mitochondrial optic neuropathies Tomography X-Ray Computed MESH: Female 030217 neurology & neurosurgery |
| Zdroj: | Brain-A Journal of Neurology Brain-A Journal of Neurology, Oxford University Press (OUP), 2008, 131 (Pt 2), pp.338-51. ⟨10.1093/brain/awm298⟩ Brain-A Journal of Neurology, 2008, 131 (Pt 2), pp.338-51. ⟨10.1093/brain/awm298⟩ Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0006-8950 1460-2156 |
| DOI: | 10.1093/brain/awm298⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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