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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease
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Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease

机译：人类线粒体疾病突变体tRNA的摆动修饰缺陷引起的密码子特异性翻译缺陷

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摘要

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.
机译：线粒体（mt）tRNA（Leu（UUR））基因中的点突变负责线粒体肌病，脑病，乳酸性酸中毒和中风样发作（MELAS），这是线粒体脑肌病的一个子类。我们先前显示，来自MELAS患者的具有A3243G或T3271C突变的mt tRNA（Leu（UUR））在反密码子摆动位置缺乏正常的含牛磺酸修饰物（taum5U; 5-taurinomethyluridine）。为了检查由于摆动修饰缺陷而导致的突变tRNA的解码失调，而独立于致病性点突变本身，我们使用了分子手术技术来构建缺少牛磺酸修饰但没有致病性突变的mt tRNA（Leu（UUR））分子。没有牛磺酸修饰的这种“操作的” mt tRNA（Leu（UUR））显示UUG翻译严重减少，但UUA翻译没有减少。因此，我们得出结论，突变体mt tRNA（Leu（UUR））的UUG密码子特异性翻译缺陷是在分子水平上引起MELAS的主要原因。该结果可以解释在MELAS中临床观察到的复杂的I缺乏症。

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