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Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Lookup NU author(s): David Moore, Professor Patrick Chinnery, Dr Patrick Yu Wai Man


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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.

Publication metadata

Author(s): Angebault C, Guichet PO, Talmat-Amar Y, Charif M, Gerber S, Fares-Taie L, Gueguen N, Halloyn F, Moore D, Amati-Bonneau P, Manes G, Hebrard M, Bocquet B, Quiles M, Piro-Megy 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

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2015

Volume: 97

Issue: 5

Pages: 754-760

Print publication date: 05/11/2015

Online publication date: 22/10/2015

Acceptance date: 25/09/2015

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2015.09.012


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