title: Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies.
abstract: Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Angebault
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Guichet
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Talmat-Amar
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France; INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France.
authors.forename: Majida
authors.initials: M
authors.lastname: Charif
authors.affiliation: INSERM U1163, Hôpital Necker Enfants-Malades, 75015 Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerber
authors.affiliation: INSERM U1163, Hôpital Necker Enfants-Malades, 75015 Paris, France.
authors.forename: Lucas
authors.initials: L
authors.lastname: Fares-Taie
authors.affiliation: INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France.
authors.forename: Naig
authors.initials: N
authors.lastname: Gueguen
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: François
authors.initials: F
authors.lastname: Halloy
authors.affiliation: Institute of Genetic Medicine, Centre for Life, Newcastle University and Wellcome Trust Centre for Mitochondrial Research, NE1 3BZ Newcastle upon Tyne, UK.
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.affiliation: INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Amati-Bonneau
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Gael
authors.initials: G
authors.lastname: Manes
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Hebrard
authors.affiliation: Centre de Référence pour les Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, CHRU Montpellier, 34090 Montpellier, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Bocquet
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Quiles
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Piro-Mégy
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Marisa
authors.initials: M
authors.lastname: Teigell
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Delettre
authors.affiliation: INSERM U710, Laboratoire MMDN EPHE, 34090 Montpellier, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Rossel
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France; Centre de Référence pour les Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, CHRU Montpellier, 34090 Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Meunier
authors.affiliation: Department of Ophthalmology, Justus-Liebig University, 35392 Giessen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Preising
authors.affiliation: Department of Ophthalmology, Justus-Liebig University, 35392 Giessen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Lorenz
authors.affiliation: IRCCS, Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy; Department of Biomedical and NeuroMotor Sciences, University of Bologna, 40139 Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.affiliation: Institute of Genetic Medicine, Centre for Life, Newcastle University and Wellcome Trust Centre for Mitochondrial Research, NE1 3BZ Newcastle upon Tyne, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Institute of Genetic Medicine, Centre for Life, Newcastle University and Wellcome Trust Centre for Mitochondrial Research, NE1 3BZ Newcastle upon Tyne, UK; Newcastle Eye Centre, Royal Victoria Infirmary, NE1 4LP Newcastle upon Tyne, UK.
authors.forename: Patrick
authors.initials: P
authors.lastname: Yu-Wai-Man
authors.affiliation: INSERM U1163, Hôpital Necker Enfants-Malades, 75015 Paris, France.
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France; Centre de Référence pour les Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, CHRU Montpellier, 34090 Montpellier, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Département de Recherche Scientifique, Institut Pasteur du Maroc, 20360 Casablanca, Morocco.
authors.forename: Abdelhamid
authors.initials: A
authors.lastname: Barakat
authors.affiliation: INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: INSERM U1163, Hôpital Necker Enfants-Malades, 75015 Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Bomont
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France; Centre de Référence pour les Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, CHRU Montpellier, 34090 Montpellier, France.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
authors.affiliation: INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France; INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France. Electronic address: guy.lenaers@inserm.fr.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D042967:Electron Transport Complex I; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005500:Follow-Up Studies; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration; D009901:Optic Nerve Diseases / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D011379:Prognosis; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; C459094:RTN4IP1 protein, human; D042967:Electron Transport Complex I