The MFN2 Gene Is Responsible for Mitochondrial DNA Instability and Optic Atrophy 'Plus' Phenotype

Brain. 2012 Jan;135(Pt 1):23-34. doi: 10.1093/brain/awr323. Epub 2011 Dec 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • DNA Damage
  • DNA, Mitochondrial / genetics*
  • DNA, Mitochondrial / metabolism
  • Female
  • GTP Phosphohydrolases / genetics*
  • GTP Phosphohydrolases / metabolism
  • Humans
  • Male
  • Middle Aged
  • Mitochondrial Myopathies / complications
  • Mitochondrial Myopathies / genetics*
  • Mitochondrial Myopathies / metabolism
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Mutation, Missense
  • Optic Atrophy / complications
  • Optic Atrophy / genetics*
  • Optic Atrophy / metabolism
  • Pedigree

Substances

  • DNA, Mitochondrial
  • Mitochondrial Proteins
  • GTP Phosphohydrolases
  • MFN2 protein, human