Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs
Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs
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DOI：
10.1086/508434
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发表时间：
2006-11-01
影响因子：
9.8
通讯作者：
Shoubridge, Eric A.
中科院分区：
文献类型：
--
作者：
Smeitink, Jan A. M.;Elpeleg, Orly;Shoubridge, Eric A.
线粒体DNA（mtDNA）中编码的13种多肽在线粒体基质中在一个专用的蛋白质翻译装置上合成，该装置类似于原核生物中发现的装置。在这里，我们已经调查了线粒体蛋白质合成缺陷与氧化磷酸化酶缺乏症的遗传基础，在两个病人中，其中一人提出与脑肌病和其他肥厚型心肌病。候选基因的测序显示，在TSFM，一个编码线粒体翻译延伸因子EFTs的基因中，两名患者中存在相同的纯合突变（C997 T）。EFT作为EFTu的鸟嘌呤核苷酸交换因子发挥作用，EFTu是另一种翻译延伸因子，其将氨酰化的转移RNA作为与三磷酸鸟苷的三元复合物带到核糖体A位点。突变预测Arg 333 Trp取代在进化上保守的网站在一个亚结构域的EFTs与EFTu相互作用。分子模拟表明，取代破坏了局部亚结构域和二聚界面。与对照组相比，患者成纤维细胞中EFT和EFTu的稳态水平分别降低了75%和60%，组装的复合物I、IV和V的量降低了35%-91%。这些表型和翻译缺陷被EFT或EFTu的逆转录病毒表达所拯救。这些数据清楚地表明突变EFT是这些患者的病因。相同的突变与不同的临床表型相关的事实表明线粒体翻译装置的遗传修饰剂的存在。
The 13 polypeptides encoded in mitochondrial DNA ( mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes. Here, we have investigated the genetic basis for a mitochondrial protein-synthesis defect associated with a combined oxidative phosphorylation enzyme deficiency in two patients, one of whom presented with encephalomyopathy and the other with hypertrophic cardiomyopathy. Sequencing of candidate genes revealed the same homozygous mutation (C997T) in both patients in TSFM, a gene coding for the mitochondrial translation elongation factor EFTs. EFTs functions as a guanine nucleotide exchange factor for EFTu, another translation elongation factor that brings aminoacylated transfer RNAs to the ribosomal A site as a ternary complex with guanosine triphosphate. The mutation predicts an Arg333Trp substitution at an evolutionarily conserved site in a subdomain of EFTs that interacts with EFTu. Molecular modeling showed that the substitution disrupts local subdomain structure and the dimerization interface. The steady-state levels of EFTs and EFTu in patient fibroblasts were reduced by 75% and 60%, respectively, and the amounts of assembled complexes I, IV, and V were reduced by 35%-91% compared with the amounts in controls. These phenotypes and the translation defect were rescued by retroviral expression of either EFTs or EFTu. These data clearly establish mutant EFTs as the cause of disease in these patients. The fact that the same mutation is associated with distinct clinical phenotypes suggests the presence of genetic modifiers of the mitochondrial translation apparatus.