2. Academic Validation
  3. Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission

Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission

  • Brain. 2017 Oct 1;140(10):2586-2596. doi: 10.1093/brain/awx219.
Sylvie Gerber # 1,  Majida Charif # 2,  Arnaud Chevrollier 2,  Tanguy Chaumette 2,  Claire Angebault 3,  Mariame Selma Kane 2,  Aurélien Paris 2,  Jennifer Alban 2,  Mélanie Quiles 3,  Cécile Delettre 3,  Dominique Bonneau 2,  Vincent Procaccio 2,  Patrizia Amati-Bonneau 2,  Pascal Reynier 2,  Stéphanie Leruez 2,  Raphael Calmon 4,  Nathalie Boddaert 5,  Benoit Funalot 5,  Marlène Rio 5,  Didier Bouccara 6,  Isabelle Meunier 3,  Hiromi Sesaki 7,  Josseline Kaplan 1,  Christian P Hamel 3,  Jean-Michel Rozet # 1,  Guy Lenaers # 2
Affiliations

Affiliations

  • 1 Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
  • 2 MitoLab, Mitochondrial Medicine Research Centre, UMR CNRS 6015-INSERM 1083, Institut MitoVasc, University of Angers, 49933 Angers, France.
  • 3 Institut des Neurosciences de Montpellier, INSERM U1051, Université de Montpellier, France.
  • 4 Department of Pediatric Neurology, IHU Necker Enfants Malades and Image at Imagine, INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.
  • 5 Department of Genetics, IHU Necker-Enfants Malades, University Paris Descartes, 75015 Paris, France; Department of Genetics, GHU Henri Mondor, 94010 Créteil, France.
  • 6 Service d'ORL, Hôpital Universitaire Pitié-Salpêtrière, 75013 Paris, France.
  • 7 Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • # Contributed equally.
PMID: 28969390 DOI: 10.1093/brain/awx219
Abstract

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.

Keywords

DNM1L; DRP1; OPA1; dominant optic atrophy; mitochondria.

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