Mutations in C12orf65 in Patients with Encephalomyopathy and a Mitochondrial Translation Defect
Mutations in C12orf65 in Patients with Encephalomyopathy and a Mitochondrial Translation Defect
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DOI：
10.1016/j.ajhg.2010.06.004
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发表时间：
2010-07-09
影响因子：
9.8
通讯作者：
Shoubridge, Eric A.
中科院分区：
文献类型：
--
作者：
Antonicka, Hana;Ostergaard, Elsebet;Shoubridge, Eric A.
我们调查了来自两个不相关家系的患者的成纤维细胞线粒体转译整体一致减少的遗传学基础，这些患者发展为Leigh综合征、视神经萎缩和眼肌麻痹。氧化磷酸化复合体的组装分析表明，复合体I、IV和V的组装严重减少，复合体III的降幅较小。线粒体mRNAs、tRNAs和rRNAs的稳态水平没有降低，线粒体翻译延长因子和线粒体核糖体的蛋白质组分的水平也没有降低。利用纯合图谱，我们在1例患者中发现了C12orf65基因的1个碱基缺失，而DNA序列分析在第二个患者中发现了不同的1个碱基缺失。这两个突变预示着相同的过早终止密码子。C12orf65属于一个由四个线粒体I类多肽释放因子组成的家族，它还包括mtRF1a、mtRF1和Ict1，它们的特征都是在活性部位存在一个GGQ基序。然而，在细菌核糖体的体外试验中，C12orf65不表现出肽基-tRNA水解酶活性。我们认为，它可能在回收在翻译延伸阶段从核糖体释放的流产的多肽-tRNA物种中发挥作用。
We investigated the genetic basis for a global and uniform decrease in mitochondrial translation in fibroblasts from patients in two unrelated pedigrees who developed Leigh syndrome, optic atrophy, and ophthalmoplegia. Analysis of the assembly of the oxidative phosphorylation complexes showed severe decreases of complexes I, IV, and V and a smaller decrease in complex III. The steady-state levels of mitochondrial mRNAs, tRNAs, and rRNAs were not reduced, nor were those of the mitochondrial translation elongation factors or the protein components of the mitochondrial ribosome. Using homozygosity mapping, we identified a 1 bp deletion in C12orf65 in one patient, and DNA sequence analysis showed a different 1 bp deletion in the second patient. Both mutations predict the same premature stop codon. C12orf65 belongs to a family of four mitochondrial class I peptide release factors, which also includes mtRF1a, mtRF1, and Ict1, all characterized by the presence of a GGQ motif at the active site. However, C12orf65 does not exhibit peptidyl-tRNA hydrolase activity in an in vitro assay with bacterial ribosomes. We suggest that it might play a role in recycling abortive peptidyl-tRNA species, released from the ribosome during the elongation phase of translation.