title: Mutations in mitochondrial-encoded cytochrome c oxidase subunits I, II, and III genes detected in Alzheimer's disease using single-strand conformation polymorphism.
abstract: A "mitochondrial hypothesis" of late onset Alzheimer's disease (AD) has been proposed. Biochemical studies indicate that there is a significant decrease in cytochrome oxidase (CO) activity as well as perturbed CO I and CO III mRNA levels in platelets and brain tissue from Alzheimer's patients. Using the electrophoretic mutation detection technique SSCP and DNA sequencing, we have identified 20 point mutations in the mitochondrial-encoded CO subunits (CO I, II, and III) in AD and age-matched control brain samples. Eight of the mutations are new variants of the mitochondrial genome. The efficiency of SSCP in detecting mutations in the CO subunits was estimated to be 80% when compared to dideoxy sequencing. One of the mutations (at position 9,861) results in a phenylalanine-->leucine substitution at a highly conserved residue in CO III. CO activity was reduced by an average of 35% in all AD brains compared to age-matched control samples, which agrees with previous reports. CO activity in one of the AD brain samples carrying the 9,861 mutation decreased by 80% relative to control brain samples, suggesting that the phenotypic expression of this mutation may result in reduced CO activity and compromised mitochondrial function.
authors.affiliation: Laboratory of Molecular Biochemistry, Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA 23507-1696, USA.
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Hamblet
authors.forename: Brian
authors.initials: B
authors.lastname: Ragland
authors.forename: Mervat
authors.initials: M
authors.lastname: Ali
authors.forename: Barbara
authors.initials: B
authors.lastname: Conyers
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Castora
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics*; D004587:Electrophoresis, Agar Gel; D050259:Genes, Mitochondrial; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D021122:Protein Subunits / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D021122:Protein Subunits; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV