title: Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease.
abstract: OBJECTIVE
  Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).
  
  
  METHODS
  A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function.
  
  
  RESULTS
  Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme.
  
  
  CONCLUSIONS
  We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.
authors.affiliation: From the MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Murphy
authors.forename: Ellen
authors.initials: E
authors.lastname: Cottenie
authors.forename: Annapurna
authors.initials: A
authors.lastname: Chalasani
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.forename: Cathy
authors.initials: C
authors.lastname: Woodward
authors.forename: Ese E
authors.initials: EE
authors.lastname: Mudanohwo
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.forename: Simon
authors.initials: S
authors.lastname: Heales
authors.forename: John
authors.initials: J
authors.lastname: Land
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.forename: Michael
authors.initials: M
authors.lastname: Champion
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Robb
authors.forename: Rupert
authors.initials: R
authors.lastname: Page
authors.forename: Michael
authors.initials: M
authors.lastname: Rose
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.forename: Carol
authors.initials: C
authors.lastname: Crowe
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lunn
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004272:DNA, Mitochondrial; D005260:Female; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree
chemical_list: D004272:DNA, Mitochondrial; C501005:MT-ATP6 protein, human; D025261:Mitochondrial Proton-Translocating ATPases