Recessive mutations in RTN4IP1 cause isolated and syndromic optic neuropathies
Angebault C., Guichet PO., Talmat-Amar Y., Charif M., Gerber S., Fares-Taie L., Gueguen N., Halloy F., Moore D., Amati-Bonneau P., Manes G., Hebrard M., Bocquet B., Quiles M., Piro-Mégy C., Teigell M., Delettre C., Rossel M., Meunier I., Preising M., Lorenz B., Carelli V., Chinnery PF., Yu-Wai-Man P., Kaplan J., Roubertie A., Barakat A., Bonneau D., Reynier P., Rozet JM., Bomont P., Hamel CP., Lenaers G.
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.