Codon-specific Translational Defect Caused by a Wobble Modification Deficiency in Mutant TRNA from a Human Mitochondrial Disease

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Oct 13

PMID 15477592

Citations 114

Authors

Yohei Kirino

Takehiro Yasukawa

Shigeo Ohta

Shigeo Akira

Kaisuke Ishihara

Kimitsuna Watanabe

Tsutomu Suzuki

Affiliations

Soon will be listed here.

Abstract

Point mutations in the mitochondrial (mt) tRNA(Leu(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 tRNA(Leu(UUR)) with an A3243G or T3271C mutation derived from patients with MELAS are deficient in a normal taurine-containing modification (taum5U; 5-taurinomethyluridine) at the anticodon wobble position. To examine decoding disorder of the mutant tRNA due to the wobble modification deficiency independent of the pathogenic point mutation itself, we used a molecular surgery technique to construct an mt tRNA(Leu(UUR)) molecule lacking the taurine modification but without the pathogenic mutation. This "operated" mt tRNA(Leu(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 tRNAs(Leu(UUR)) is the primary cause of MELAS at the molecular level. This result could explain the complex I deficiency observed clinically in MELAS.

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