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: Claire Angebault, Pierre-Olivier Guichet, Yasmina Talmat-Amar, Majida Charif, Sylvie Gerber, Lucas Fares-Taie, Naig Gueguen, François Halloy, David Moore, Patrizia Amati-Bonneau, Gael Manes, Maxime Hebrard, Béatrice Bocquet, Mélanie Quiles, Camille Piro-Mégy, Marisa Teigell, Cécile Delettre, Mireille Rossel, Isabelle Meunier, Markus Preising, Birgit Lorenz, Valerio Carelli, Patrick F Chinnery, Patrick Yu-Wai-Man, Josseline Kaplan, Agathe Roubertie, Abdelhamid Barakat, Dominique Bonneau, Pascal Reynier, Jean-Michel Rozet, Pascale Bomont, Christian P Hamel, Guy Lenaers
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 97 Issue 5 Pg. 754-60 (Nov 05 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 26593267 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• Mitochondrial Proteins
• RTN4IP1 protein, human
• Electron Transport Complex I

Topics

• Amino Acid Sequence
• Animals
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Case-Control Studies
• Cells, Cultured
• Electron Transport Complex I
• Female
• Fibroblasts (metabolism, pathology)
• Follow-Up Studies
• Genes, Recessive
• Humans
• Male
• Mice
• Mitochondria (genetics, pathology)
• Mitochondrial Proteins (antagonists & inhibitors, genetics, metabolism)
• Molecular Sequence Data
• Mutation (genetics)
• Nerve Degeneration
• Optic Nerve Diseases (genetics, pathology)
• Pedigree
• Prognosis
• Retinal Ganglion Cells (metabolism, pathology)
• Sequence Homology, Amino Acid
• Zebrafish (genetics, growth & development, metabolism)