title: Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.
abstract: OBJECTIVE
  Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified.
  
  
  METHODS
  We here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation. Using a variety of methods we investigated the possibility of mitochondrial impairment in the patients cell lines.
  
  
  RESULTS
  We described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene. We report mitochondrial impairment in the patients cell lines, followed by multiple lines of evidence which include decrease of complex V activity and stability (blue native gel assay), decrease in mitochondrial respiration rate and reduction of mitochondrial membrane potential.
  
  
  CONCLUSIONS
  This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.
authors.affiliation: Department of Molecular Neuroscience and Reta Lila Weston Research Laboratories, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, , London, UK.
authors.forename: Arianna
authors.initials: A
authors.lastname: Tucci
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Preza
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.forename: Annapurna
authors.initials: A
authors.lastname: Chalasani
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: John M
authors.initials: JM
authors.lastname: Land
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
authors.forename: Zane
authors.initials: Z
authors.lastname: Jaunmuktane
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010454:Peptide Termination Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics; D055815:Young Adult
chemical_list: D020558:GTP Phosphohydrolases; D024101:Mitochondrial Proteins; D010454:Peptide Termination Factors; D012268:Ribose-Phosphate Pyrophosphokinase; C551030:MTRFR protein, human; C510474:PRPS1 protein, human; C470018:MFN2 protein, human
keywords: Genetics; Neuropathy