Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies PMID: 26593267

ADC Targets in Oncology

2026-04-10

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

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: [email protected].

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.