title: The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype.
abstract: 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.
authors.affiliation: Department of Medical Genetics, National Centre for Mitochondrial Diseases, Nice Teaching Hospital, 06200, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rouzier
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bannwarth
authors.forename: Annabelle
authors.initials: A
authors.lastname: Chaussenot
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevrollier
authors.forename: Annie
authors.initials: A
authors.lastname: Verschueren
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonello-Palot
authors.forename: Konstantina
authors.initials: K
authors.lastname: Fragaki
authors.forename: Aline
authors.initials: A
authors.lastname: Cano
authors.forename: Jean
authors.initials: J
authors.lastname: Pouget
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pellissier
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.forename: Brigitte
authors.initials: B
authors.lastname: Chabrol
authors.forename: Véronique
authors.initials: V
authors.lastname: Paquis-Flucklinger
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009896:Optic Atrophy / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human