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.
|Number of pages
|Proceedings of the National Academy of Sciences of the United States of America
|Published - Oct 19 2004
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