TY - JOUR
T1 - Mutations in DNM1L, as in OPA1, result indominant optic atrophy despite opposite effectson mitochondrial fusion and fission
AU - Gerber, Sylvie
AU - Charif, Majida
AU - Chevrollier, Arnaud
AU - Chaumette, Tanguy
AU - Angebault, Claire
AU - Kane, Mariame Selma
AU - Paris, Aurcrélien
AU - Alban, Jennifer
AU - Quiles, McRélanie
AU - Delettre, Ccrécile
AU - Bonneau, Dominique
AU - Procaccio, Vincent
AU - Amati-Bonneau, Patrizia
AU - Reynier, Pascal
AU - Leruez, Stcréphanie
AU - Calmon, Raphael
AU - Boddaert, Nathalie
AU - Funalot, Benoit
AU - Rio, Marlène
AU - Bouccara, Didier
AU - Meunier, Isabelle
AU - Sesaki, Hiromi
AU - Kaplan, Josseline
AU - Hamel, Christian P.
AU - Rozet, Jean Michel
AU - Lenaers, Guy
N1 - Funding Information:
We are indebted for the financial support of the Université d’Angers, CHU d’Angers, the Région Pays de la Loire, Angers Loire Métropole, the Fondation Maladies Rares, Fondation pour la Recherche Médicale, Retina France, UNADEV, Association Franc¸aise contre les Myopathies, Ouvrir Les Yeux, Kjer-France and the Fondation VISIO.
Publisher Copyright:
© The Author (2017).
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
KW - DNM1L
KW - DRP1
KW - OPA1
KW - dominant optic atrophy
KW - mitochondria
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U2 - 10.1093/brain/awx219
DO - 10.1093/brain/awx219
M3 - Article
C2 - 28969390
AN - SCOPUS:85030671935
SN - 0006-8950
VL - 140
SP - 2586
EP - 2596
JO - Brain
JF - Brain
IS - 10
ER -