2. Academic Validation
  3. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

  • Am J Hum Genet. 2015 Nov 5;97(5):754-60. doi: 10.1016/j.ajhg.2015.09.012.
Claire Angebault 1,  Pierre-Olivier Guichet 1,  Yasmina Talmat-Amar 1,  Majida Charif 2,  Sylvie Gerber 3,  Lucas Fares-Taie 3,  Naig Gueguen 4,  François Halloy 1,  David Moore 5,  Patrizia Amati-Bonneau 4,  Gael Manes 1,  Maxime Hebrard 1,  Béatrice Bocquet 6,  Mélanie Quiles 1,  Camille Piro-Mégy 1,  Marisa Teigell 1,  Cécile Delettre 1,  Mireille Rossel 7,  Isabelle Meunier 8,  Markus Preising 9,  Birgit Lorenz 9,  Valerio Carelli 10,  Patrick F Chinnery 5,  Patrick Yu-Wai-Man 11,  Josseline Kaplan 3,  Agathe Roubertie 8,  Abdelhamid Barakat 12,  Dominique Bonneau 4,  Pascal Reynier 4,  Jean-Michel Rozet 3,  Pascale Bomont 1,  Christian P Hamel 8,  Guy Lenaers 13
Affiliations

Affiliations

  • 1 INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France.
  • 2 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.
  • 3 INSERM U1163, Hôpital Necker Enfants-Malades, 75015 Paris, France.
  • 4 INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France.
  • 5 Institute of Genetic Medicine, Centre for Life, Newcastle University and Wellcome Trust Centre for Mitochondrial Research, NE1 3BZ Newcastle upon Tyne, UK.
  • 6 Centre de Référence pour les Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac, CHRU Montpellier, 34090 Montpellier, France.
  • 7 INSERM U710, Laboratoire MMDN EPHE, 34090 Montpellier, France.
  • 8 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.
  • 9 Department of Ophthalmology, Justus-Liebig University, 35392 Giessen, Germany.
  • 10 IRCCS, Institute of Neurological Sciences of Bologna, Bellaria Hospital, 40139 Bologna, Italy; Department of Biomedical and NeuroMotor Sciences, University of Bologna, 40139 Bologna, Italy.
  • 11 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.
  • 12 Laboratoire de Génétique Moléculaire Humaine, Département de Recherche Scientifique, Institut Pasteur du Maroc, 20360 Casablanca, Morocco.
  • 13 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.
PMID: 26593267 DOI: 10.1016/j.ajhg.2015.09.012
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.

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