title: Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
abstract: The mitochondrial tRNA(Leu)(UUR) (R = A or G) gene possesses several hot spots for pathogenic mutations. A point mutation at nucleotide position 3243 or 3271 is associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes and maternally inherited diabetes with deafness. Detailed studies on two tRNAs(Leu)(UUR) with the 3243 or 3271 mutation revealed some common characteristics in cybrid cells: (i) a decreased life span, resulting in a 70% decrease in the amounts of the tRNAs in the steady state, (ii) a slight decrease in the ratios of aminoacyl-tRNAs(Leu)(UUR) versus uncharged tRNAs(Leu)(UUR), and (iii) accurate aminoacylation with leucine without any misacylation. As a marked result, both of the mutant tRNA molecules were deficient in a modification of uridine that occurs in the normal tRNA(Leu)(UUR) at the first position of the anticodon. The lack of this modification may lead to the mistranslation of leucine into non-cognate phenylalanine codons by mutant tRNAs(Leu)(UUR), according to the mitochondrial wobble rule, and/or a decrease in the rate of mitochondrial protein synthesis. This finding could explain why two different mutations (3243 and 3271) manifest indistinguishable clinical features.
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yasukawa
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: S
authors.initials: S
authors.lastname: Ohta
authors.forename: K
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D000926:Anticodon / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics*; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D009705:Nucleosides / Q000032:analysis; D017354:Point Mutation; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu / Q000032:analysis / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: D000926:Anticodon; D004272:DNA, Mitochondrial; D009705:Nucleosides; D000077278:RNA, Mitochondrial; D012356:RNA, Transfer, Leu; D012313:RNA