Weraarpachai Woranontee, Antonicka Hana, Sasarman Florin, Seeger Jürgen, Schrank Bertold, Kolesar Jill E, Lochmüller Hanns, Chevrette Mario, Kaufman Brett A, Horvath Rita, Shoubridge Eric A
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Nat Genet. 2009 Jul;41(7):833-7. doi: 10.1038/ng.390. Epub 2009 Jun 7.
Defects in mitochondrial translation are among the most common causes of mitochondrial disease, 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. As mammalian mitochondrial mRNAs do not have significant 5' UTRs, 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, and our findings suggest that it is one of a family of specific mammalian mitochondrial translational activators.
线粒体翻译缺陷是线粒体疾病最常见的病因之一，但调节线粒体翻译的机制仍 largely 未知。在酿酒酵母中，所有线粒体 mRNA 都需要特定的翻译激活因子，这些因子识别 5' UTR 中的序列并介导翻译。由于哺乳动物线粒体 mRNA 没有显著的 5' UTR，因此必须存在其他机制来促进翻译。我们在一个分离迟发性 Leigh 综合征和细胞色素 c 氧化酶（COX）缺乏症的家系中，鉴定出线粒体 DNA（mtDNA）编码的 COX I 亚基合成存在特定缺陷。我们通过功能互补将该缺陷定位到 17 号染色体，并在编码含有保守 DUF28 结构域的一大类假设蛋白家族成员的 CCDC44 中鉴定出一个纯合单碱基对插入。CCDC44 因 COX I 的翻译激活因子而重命名为 TACO1，与细菌同源物具有显著程度的结构相似性，我们的研究结果表明它是特定哺乳动物线粒体翻译激活因子家族的一员。
