Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission

Sylvie Gerber, Majida Charif, Arnaud Chevrollier, Tanguy Chaumette, Claire Angebault, Mariame Selma Kane, Aurcrélien Paris, Jennifer Alban, McRélanie Quiles, Ccrécile Delettre, Dominique Bonneau, Vincent Procaccio, Patrizia Amati-Bonneau, Pascal Reynier, Stcréphanie Leruez, Raphael Calmon, Nathalie Boddaert, Benoit Funalot, Marlène Rio, Didier BouccaraIsabelle Meunier, Hiromi Sesaki, Josseline Kaplan, Christian P. Hamel, Jean Michel Rozet, Guy Lenaers

Research output: Contribution to journalArticlepeer-review


Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l+ / mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.

Original languageEnglish (US)
Pages (from-to)2586-2596
Number of pages11
Issue number10
StatePublished - Oct 1 2017


  • DNM1L
  • DRP1
  • OPA1
  • dominant optic atrophy
  • mitochondria

ASJC Scopus subject areas

  • Clinical Neurology

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