Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease
Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease
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DOI：
10.1073/pnas.0405173101
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发表时间：
2004-10-19
影响因子：
11.1
通讯作者：
Suzuki, T
中科院分区：
文献类型：
--
作者：
Kirino, Y;Yasukawa, T;Suzuki, T
线粒体（mt）tRNA（Leu（UUR））基因的点突变导致线粒体肌病、脑病、乳酸酸中毒和卒中样发作（MELAS），这是线粒体脑肌病疾病的一个亚组。我们以前发现，来自MELAS患者的带有A3243 G或T3271 C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（taum（5）U; 5-牛磺酸甲基尿苷）。为了研究由于摆动修饰缺陷而导致的突变型tRNA的解码障碍，我们使用分子外科技术构建了缺乏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，UUG密码子特异性翻译缺陷的突变mt tRNA（Leu（UUR））是主要原因的MELAS在分子水平上。这一结果可以解释在MELAS中临床观察到的复合物1缺陷。
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 (taum(5)U; 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 1 deficiency observed clinically in MELAS.