Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome
Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome
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DOI：
10.1038/ng.390
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发表时间：
2009-07-01
期刊：
影响因子：
30.8
通讯作者：
Shoubridge, Eric A.
中科院分区：
文献类型：
--
作者：
Weraarpachai, Woranontee;Antonicka, Hana;Shoubridge, Eric A.
线粒体翻译缺陷是线粒体疾病最常见的原因之一（1），但调节线粒体翻译的机制在很大程度上仍然未知。在酵母酿酒酵母中，所有线粒体mRNA都需要特异性翻译激活剂，其识别5'UTR中的序列并介导翻译（2）。由于哺乳动物线粒体mRNA没有显著的5'UTR（3），因此必须存在替代机制来促进翻译。我们发现了一个分离晚发型Leigh综合征和细胞色素c氧化酶（考克斯）缺乏症的家系中线粒体DNA（mtDNA）编码的考克斯I亚基合成的特定缺陷。我们通过功能互补将缺陷定位到染色体17 q，并在CCDC 44中鉴定了纯合的单碱基对插入，编码含有保守DUF28结构域的假设蛋白质大家族的成员。CCDC 44，因考克斯I的翻译激活因子而更名为TACO 1，与细菌同系物具有显著程度的结构相似性（4），我们的发现表明它是特定哺乳动物线粒体翻译激活因子家族中的一员。
Defects in mitochondrial translation are among the most common causes of mitochondrial disease(1), but the mechanisms that regulate mitochondrial translation remain largely unknown. In the yeast Saccharomyces cerevisiae, all mitochondrial mRNAs require specific translational activators, which recognize sequences in 5' UTRs and mediate translation(2). As mammalian mitochondrial mRNAs do not have significant 5' UTRs(3), alternate mechanisms must exist to promote translation. We identified a specific defect in the synthesis of the mitochondrial DNA (mtDNA)-encoded COX I subunit in a pedigree segregating late-onset Leigh syndrome and cytochrome c oxidase (COX) deficiency. We mapped the defect to chromosome 17q by functional complementation and identified a homozygous single-base-pair insertion in CCDC44, encoding a member of a large family of hypothetical proteins containing a conserved DUF28 domain. CCDC44, renamed TACO1 for translational activator of COX I, shares a notable degree of structural similarity with bacterial homologs(4), and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.