March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Mitofusin 2 (MFN2) Mutations Cause Mitochondrial DNA Instability In Charcot-Marie-Tooth Disease
Author Affiliations & Notes
  • Patrick Yu-Wai-Man
    Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    Department of Ophthalmology,
    Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
  • Kamil S. Sitarz
    Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
  • Joanna D. Stewart
    Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    IfADo - Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany
  • Angela Pyle
    Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
  • Bernd Rautenstrauss
    Medical Genetics Center, Munich, Germany
  • Pavel Seeman
    Department of Child Neurology, Charles University, Prague, Czech Republic
  • Rita Horvath
    Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    Department of Neurology,
    Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
  • Patrick F. Chinnery
    Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
    Department of Neurology,
    Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
  • Footnotes
    Commercial Relationships  Patrick Yu-Wai-Man, None; Kamil S. Sitarz, None; Joanna D. Stewart, None; Angela Pyle, None; Bernd Rautenstrauss, None; Pavel Seeman, None; Rita Horvath, None; Patrick F. Chinnery, None
  • Footnotes
    Support  Medical Research Council (MRC, UK) and the Wellcome Trust
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1310. doi:https://doi.org/
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      Patrick Yu-Wai-Man, Kamil S. Sitarz, Joanna D. Stewart, Angela Pyle, Bernd Rautenstrauss, Pavel Seeman, Rita Horvath, Patrick F. Chinnery; Mitofusin 2 (MFN2) Mutations Cause Mitochondrial DNA Instability In Charcot-Marie-Tooth Disease. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1310. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral neuropathies and it affects at least 1 in 2,500 individuals. A specific autosomal-dominant axonal CMT subtype, hereditary motor and sensory neuropathy type VI (HMSN-VI, OMIM 601152), is caused by mutations in mitofusin 2 (MFN2, 1p36.2). In addition to early-onset severe peripheral neuropathy, affected individuals also develop progressive optic nerve dysfunction in later childhood. MFN2 is a critical mitochondrial outer membrane protein and it shares a remarkable degree of structural and functional complementarity with OPA1, a mitochondrial inner membrane protein implicated in the majority of cases of autosomal-dominant optic atrophy (ADOA, OMIM 165500). The aim of this study was to provide new mechanistic insights by investigating the deleterious influence of MFN2 mutations on mitochondrial biogenesis.

Methods: : Tissue samples were available from 48 patients with confirmed MFN2 mutations. Using well-established molecular protocols, various markers of mitochondrial dysfunction were assayed including: (i) mitochondrial DNA (mtDNA) proliferation in blood leukocytes, (ii) the presence of biochemically-defective cytochrome c oxidase (COX) fibers in skeletal muscle biopsies, and (iii) the kinetics of mtDNA repopulation in fibroblast cultures after ethidium bromide-induced depletion.

Results: : Blood leukocytes from MFN2-positive patients had significantly increased mtDNA copy numbers (Mean = 205.9, n = 48) compared with age-matched controls (Mean = 60.9, n = 131; p < 0.0001). Significant mtDNA proliferation was also evident in skeletal muscle fibers from MFN2-positive patients. COX-negative skeletal muscle fibers were present and these harboured high levels of somatic mtDNA deletions, accounting for the observed respiratory chain defect. MFN2-positive fibroblasts had significantly impaired rates of mtDNA repopulation following a period of increased cellular stress.

Conclusions: : The MFN2 protein is intricately involved in mtDNA maintenance and the faithful replication of the mitochondrial genome. Pathogenic MFN2 mutations ultimately lead to neuronal cell loss by triggering a mitochondrial biochemical defect.

Keywords: mitochondria • neuro-ophthalmology: optic nerve • genetics 
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