title: Accumulation of somatic nucleotide substitutions in mitochondrial DNA associated with the 3243 A-to-G tRNA(leu)(UUR) mutation in encephalomyopathy and cardiomyopathy.
abstract: To understand the pathogenesis of mitochondrial encephalomyopathy and cardiomyopathy, we analyzed the sequence heterogeneity of the skeletal muscle mitochondrial DNA from a patient with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). A mtDNA segment of 347 bp amplified from the total DNA was cloned into a vector. Analysis of 60 independent clones (20,800 bp in total) revealed the 3243 A-->G transition in all the sequenced clones and additional nucleotide substitutions at 5 sites in 10 clones. The frequency of mutant clones (10/60) in the MELAS patient was significantly higher [chi2 = 10.909, P < 0.05] than that in an age-matched skeletal muscle control (0/60) as well as in a normal placenta (2/60). These results support our hypothesis that secondary somatic mtDNA mutations can be initiated by the 3243 A-->G mutation and that the accumulation of somatic mutation in individuals with deleterious inherited mitochondrial genotype can contribute to the progressive mitochondrial dysfunction in MELAS.
authors.affiliation: Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan.
authors.forename: S A
authors.initials: SA
authors.lastname: Kovalenko
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Yoneda
authors.forename: A F
authors.initials: AF
authors.lastname: Iakovlev
authors.forename: T
authors.initials: T
authors.lastname: Ozawa
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D001706:Biopsy; D003062:Codon; D017931:DNA Primers; D004272:DNA, Mitochondrial / Q000737:chemistry* / Q000378:metabolism; D005260:Female; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010920:Placenta; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012356:RNA, Transfer, Leu / Q000096:biosynthesis / Q000235:genetics*; D012016:Reference Values
chemical_list: D003062:Codon; D017931:DNA Primers; D004272:DNA, Mitochondrial; D012356:RNA, Transfer, Leu