title: Identification and biochemical characterization of the novel mutation m.8839G>C in the mitochondrial ATP6 gene associated with NARP syndrome.
abstract: Mutations in the ATP6 gene are reported to be associated with Leber hereditary optic neuropathy, bilateral striatal necrosis, coronary atherosclerosis risk and neuropathy, ataxia and retinitis pigmentosa (NARP)/maternally inherited Leigh syndromes. Here, we present a patient with NARP syndrome, in whom a previously undescribed mutation was detected in the ATP6 gene: m.8839G>C. Several observations support the concept that m.8839G>C is pathogenically involved in the clinical phenotype of this patient: (1) the mutation was heteroplasmic in muscle; (2) mutation load was higher in the symptomatic patient than in the asymptomatic carriers; (3) cybrids carrying this mutation presented lower cell proliferation, increased mitochondrial DNA (mtDNA) copy number, increased steady-state OxPhos protein levels and decreased mitochondrial membrane potential with respect to isogenic wild-type cybrids; (4) this change was not observed in 2959 human mtDNAs from different mitochondrial haplogroups; (5) the affected amino acid was conserved in all the ATP6 sequences analyzed; and (6) using in silico prediction, the mutation was classified as 'probably damaging'. However, measurement of ATP synthesis showed no differences between wild-type and mutated cybrids. Thus, we suggest that m.8839G>C may lower the efficiency between proton translocation within F0 and F1 rotation, required for ATP synthesis. Further experiments are needed to fully characterize the molecular mechanisms involved in m.8839G>C pathogenicity.
authors.affiliation: Departament de Patología Mitocondrial i Neuromuscular, Universitari Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona.
authors.forename: A
authors.initials: A
authors.lastname: Blanco-Grau
authors.forename: I
authors.initials: I
authors.lastname: Bonaventura-Ibars
authors.forename: J
authors.initials: J
authors.lastname: Coll-Cantí
authors.forename: M J
authors.initials: MJ
authors.lastname: Melià
authors.forename: R
authors.initials: R
authors.lastname: Martinez
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Gallo
authors.forename: A L
authors.initials: AL
authors.lastname: Andreu
authors.forename: T
authors.initials: T
authors.lastname: Pinós
authors.forename: E
authors.initials: E
authors.lastname: García-Arumí
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D020125:Mutation, Missense; D010085:Oxidative Phosphorylation; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C501005:MT-ATP6 protein, human; D024101:Mitochondrial Proteins; D000255:Adenosine Triphosphate; D025261:Mitochondrial Proton-Translocating ATPases
keywords: ATP6; NARP syndrome; cybrids; mtDNA; novel mutation