The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early chil...

Full description

Saved in:
Bibliographic Details
Published in:Brain (London, England : 1878) England : 1878), 2012-01, Vol.135 (1), p.23-34
Main Authors: Rouzier, Cécile, Bannwarth, Sylvie, Chaussenot, Annabelle, Chevrollier, Arnaud, Verschueren, Annie, Bonello-Palot, Nathalie, Fragaki, Konstantina, Cano, Aline, Pouget, Jean, Pellissier, Jean-François, Procaccio, Vincent, Chabrol, Brigitte, Paquis-Flucklinger, Véronique
Format: Article
Language:English
Subjects:
Adolescent
Adult
Biological and medical sciences
Charcot-Marie-Tooth disease
Child
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
DNA Damage
DNA, Mitochondrial - genetics
DNA, Mitochondrial - metabolism
Female
GTP Phosphohydrolases - genetics
GTP Phosphohydrolases - metabolism
Humans
Life Sciences
Male
Medical sciences
Middle Aged
Mitochondrial Myopathies - complications
Mitochondrial Myopathies - genetics
Mitochondrial Myopathies - metabolism
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Mutation, Missense
Neurology
Optic Atrophy - complications
Optic Atrophy - genetics
Optic Atrophy - metabolism
Pedigree
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy 'plus' phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with 'mitochondrial DNA breakage' syndrome. Contrary to previous studies in patients with Charcot-Marie-Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awr323