title: Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.
abstract: OBJECTIVE
  Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive.
  
  
  METHODS
  Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed.
  
  
  RESULTS
  In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance.
  
  
  CONCLUSIONS
  MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.
authors.affiliation: Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. szuchner@duke.edu
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cherninkova
authors.forename: Steven R
authors.initials: SR
authors.lastname: Hamilton
authors.forename: Greg
authors.initials: G
authors.lastname: Van Stavern
authors.forename: Karen M
authors.initials: KM
authors.lastname: Krajewski
authors.forename: Jeffery
authors.initials: J
authors.lastname: Stajich
authors.forename: Ivajlo
authors.initials: I
authors.lastname: Tournev
authors.forename: Kristien
authors.initials: K
authors.lastname: Verhoeven
authors.forename: Christine T
authors.initials: CT
authors.lastname: Langerhorst
authors.forename: Marianne
authors.initials: M
authors.lastname: de Visser
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Thomas
authors.initials: T
authors.lastname: Bird
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Michael
authors.initials: M
authors.lastname: Shy
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D020558:GTP Phosphohydrolases; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D009431:Neural Conduction / Q000502:physiology; D009896:Optic Atrophy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D014792:Visual Acuity / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human