Recessive mutations in RTN4IP1 cause isolated and syndromic optic neuropathies

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 PreisingBirgit 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)754-760
Number of pages7
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - Nov 5 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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