title: Increased mitochondrial fusion in a autosomal recessive CMT2A family with mitochondrial GTPase mitofusin 2 mutations.
abstract: Charcot-Marie-Tooth type 2A disease (CMT2A) is an inherited peripheral neuropathy mainly caused by mutations in the MFN2 gene coding for the mitochondrial fusion protein mitofusin 2. Although the disease is mainly inherited in a dominant fashion, few cases of early-onset autosomal recessive CMT2A (AR-CMT2A) have been reported in recent years. In this study, we characterized the structure of the mitochondrial network in cultured primary fibroblasts obtained from AR-CMT2A family members. The patient-derived cells showed an increase of the mitochondrial fusion with large connected networks and an increase of the mitochondrial volume. Interestingly, fibroblasts derived from the two asymptomatic parents showed similar changes to a lesser extent. These results support the hypothesis that AR-CMT2A-related MFN2 mutations acts through a semi-dominant negative mechanism and suggest that other biological parameters might show mild alterations in asymptomatic heterozygote AR-CMT2A patients. Such alterations could be useful biomarkers helping to distinguish MFN2 mutations from variants, a growing challenge with the advent of next generation sequencing into routine clinical practice.
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Department of Neurology, University Hospital of Angers, Angers, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Codron
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevrollier
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Mariame S
authors.initials: MS
authors.lastname: Kane
authors.affiliation: Department of Neurology, University Hospital of Strasbourg, Strasbourg, France.
authors.forename: Andoni
authors.initials: A
authors.lastname: Echaniz-Laguna
authors.affiliation: Department of Neurogenetics, University Hospital of Lyon, Bron, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Department of Biochemistry and Genetics, University Hospital of Angers, Angers, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Department of Biochemistry and Genetics, University Hospital of Angers, Angers, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Department of Neurology, University Hospital of Angers, Angers, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Verny
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Department of Biochemistry and Genetics, University Hospital of Angers, Angers, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: PREMMi/Mitochondrial Medicine Research Centre, Institut MITOVASC, CNRS UMR 6214, INSERM U1083, Université d'Angers, CHU d'Angers, Angers, France.|Department of Neurology, University Hospital of Angers, Angers, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Cassereau
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D021621:Imaging, Three-Dimensional; D063154:Mitochondrial Dynamics / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D018709:Statistics, Nonparametric
chemical_list: D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human
keywords: CMT2A; autosomal recessive; mitochondrial dynamics; mitofusin 2