Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

Yohei Kirino, Takehiro Yasukawa, Shigeo Ohta, Shigeo Akira, Kaisuke Ishihara, Kimitsuna Watanabe, Tsutomu Suzuki

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Point mutations in the mitochondrial (mt) tRNALeu(UUR) gene are responsible for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), a subgroup of mitochondrial encephalomyopathic diseases. We previously showed that mt tRNALeu(UUR) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurine-containing modification (τm5U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of the mutant tRMA due to the wobble modification deficiency independent of the pathogenic point mutation itself, we used a molecular surgery technique to construct an mt tRNALeu(UUR) molecule lacking the taurine modification but without the pathogenic mutation. This "operated" mt tRNALeu(UUR) without the taurine modification showed severely reduced UUG translation but no decrease in UUA translation. We thus concluded that the UUG codon-specific translational defect of the mutant mt tRNAsLeu(UUR) is the primary cause of MELAS at the molecular level. This result could explain the complex I deficiency observed clinically in MELAS.

元の言語英語
ページ(範囲)15070-15075
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
101
発行部数42
DOI
出版物ステータス出版済み - 10 19 2004

All Science Journal Classification (ASJC) codes

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