title: 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.
authors.affiliation: Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, Angers, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.forename: Maria Esther
authors.initials: ME
authors.lastname: Gallardo
authors.forename: Belén
authors.initials: B
authors.lastname: Bornstein
authors.forename: Anne
authors.initials: A
authors.lastname: Boissière
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Campos
authors.forename: Henry
authors.initials: H
authors.lastname: Rivera
authors.forename: Jesús González
authors.initials: JG
authors.lastname: de la Aleja
authors.forename: Rosanna
authors.initials: R
authors.lastname: Carroccia
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Pierre
authors.initials: P
authors.lastname: Labauge
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelles
authors.forename: Alain
authors.initials: A
authors.lastname: Furby
authors.forename: Katell
authors.initials: K
authors.lastname: Beauvais
authors.forename: Franck
authors.initials: F
authors.lastname: Letournel
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.forename: Pasquale
authors.initials: P
authors.lastname: Montagna
authors.forename: Maria
authors.initials: M
authors.lastname: Liguori
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanna
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Andrea
authors.initials: A
authors.lastname: Cossarizza
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Christophe
authors.initials: C
authors.lastname: Verny
authors.forename: Robert
authors.initials: R
authors.lastname: Schwarzenbacher
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Martín
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arenas
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000737:chemistry / Q000648:ultrastructure; D020125:Mutation, Missense; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics / Q000473:pathology; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D013577:Syndrome; D014057:Tomography, X-Ray Computed
chemical_list: D004272:DNA, Mitochondrial; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human