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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease
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Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease

机译：突变tRNA的摆动修饰缺陷与人类线粒体疾病的临床特征之间的特定相关性

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摘要

Mutations in mtDNA are responsible for a variety of mitochondrial diseases, where the mitochondrial tRNA~(Leu(UUR)) gene has especially hot spots for pathogenic mutations. Clinical features often depend on the tRNA species and/or positions of the mutations; however, molecular pathogenesis elucidating the relation between the location of the mutations and their leading phenotype are not fully understood. We report here that mitochondrial tRNAs~(Leu(UUR)) harboring one of five mutations found in tissues from patients with symptoms of mitochondrial myopathy, encephalopathy, lactic ac-idosis, and stroke-like episodes (MELAS) (A3243G, G3244A, T3258C, T3271C, and T3291C) lacked the normal taurine-containing modification (5-taurinomethyluridine) at the anticodon wobble position. In contrast, mitochondrial tRNAs~(Leu(UUR)) with different mutations found in patients that have mitochondrial diseases but do not show the MELAS symptoms (G3242A, T3250C, C3254T, and A3280G) had the normal 5-taurinomethyluridine modifications. These observations were made by using a modified primer extension technique that can detect the modification deficiency in the extremely limited quantities of mutant tRNAs obtainable from patient tissues. These results strongly suggest deficient wobble modification could be a key molecular factor responsible for the phenotypic features of MELAS, which can explain why the different MELAS-associated mutations result in indistinguishable clinical features.
机译：线粒体DNA中的突变导致多种线粒体疾病，其中线粒体的tRNA〜（Leu（UUR））基因尤其具有致病性突变的热点。临床特征通常取决于tRNA的种类和/或突变的位置。然而，阐明突变位置与其主要表型之间关系的分子发病机理尚未完全了解。我们在这里报告线粒体tRNAs〜（Leu（UUR））携带着从患有线粒体肌病，脑病，乳酸性酸中毒和中风样发作（MELAS）症状的患者的组织中发现的五个突变之一（A3243G，G3244A，T3258C ，T3271C和T3291C）在反密码子摆动位置缺少正常的含牛磺酸修饰物（5-牛磺酸氨基甲基尿苷）。相反，在患有线粒体疾病但未显示MELAS症状（G3242A，T3250C，C3254T和A3280G）的患者中发现具有不同突变的线粒体tRNAs（Leu（UUR））具有正常的5-牛磺基甲基尿苷修饰。这些观察是通过使用改良的引物延伸技术完成的，该技术可以检测可从患者组织获得的极其有限数量的突变tRNA的修饰缺陷。这些结果强烈表明，不足的摆动修饰可能是造成MELAS表型特征的关键分子因素，这可以解释为什么与MELAS相关的不同突变会导致临床特征难以区分。

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