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

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


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

Cécile Rouzier et al. Brain. .


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.

Comment in

  • Dysfunctional mitochondrial maintenance: what breaks the circle of life?
    Yu-Wai-Man P, Chinnery PF. Yu-Wai-Man P, et al. Brain. 2012 Jan;135(Pt 1):9-11. doi: 10.1093/brain/awr352. Epub 2012 Jan 23. Brain. 2012. PMID: 22271662 No abstract available.
  • MFN2 mutations cause compensatory mitochondrial DNA proliferation.
    Sitarz KS, Yu-Wai-Man P, Pyle A, Stewart JD, Rautenstrauss B, Seeman P, Reilly MM, Horvath R, Chinnery PF. Sitarz KS, et al. Brain. 2012 Aug;135(Pt 8):e219, 1-3; author reply e220, 1-3. doi: 10.1093/brain/aws049. Epub 2012 Apr 4. Brain. 2012. PMID: 22492563 Free PMC article. No abstract available.
  • MFN2, a new gene responsible for mitochondrial DNA depletion.
    Renaldo F, Amati-Bonneau P, Slama A, Romana C, Forin V, Doummar D, Barnerias C, Bursztyn J, Mayer M, Khouri N, Billette de Villemeur T, Burglen L, Reynier P, Bernabe Gelot A, Rodriguez D. Renaldo F, et al. Brain. 2012 Aug;135(Pt 8):e223, 1-4; author reply e224, 1-3. doi: 10.1093/brain/aws111. Epub 2012 May 3. Brain. 2012. PMID: 22556188 No abstract available.

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