ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy
ELAC2 Mutations Cause a Mitochondrial RNA Processing Defect Associated with Hypertrophic Cardiomyopathy
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DOI：
10.1016/j.ajhg.2013.06.006
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发表时间：
2013-08-08
影响因子：
9.8
通讯作者：
Prokisch, Holger
中科院分区：
文献类型：
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作者：
Haack, Tobias B.;Kopajtich, Robert;Prokisch, Holger
人类线粒体基因组编码其自身翻译机制的 RNA 成分，以产生呼吸链的 13 个线粒体编码亚基。核编码基因产物对于细胞器内的所有过程（包括 RNA 加工）至关重要。线粒体基因组的转录产生大的多顺反子转录物，其间断有 22 个线粒体 (mt) tRNA，这些 tRNA 通常分别在 5' 端和 3' 端被 ELAC2 的 RNase P 复合物和 RNase Z 活性切割。我们报告了 5 名患有婴儿肥厚型心肌病和复合物 I 缺乏症的个体的 ELAC2 突变的鉴定。我们观察到受影响个体的肌肉和成纤维细胞中积累了 mtRNA 前体。尽管成纤维细胞中成熟的 mt-tRNA、mt-mRNA 和 mt-rRNA 水平并未降低，但加工缺陷与线粒体翻译受损有关。突变细胞系中的互补实验恢复了 RNA 加工，而酵母模型为缺陷 ELAC2 的疾病致病作用提供了额外的证据，从而将 mtRNA 加工与人类疾病联系起来。
The human mitochondrial genome encodes RNA components of its own translational machinery to produce the 13 mitochondrial-encoded subunits of the respiratory chain. Nuclear-encoded gene products are essential for all processes within the organelle, including RNA processing. Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 at 5' and 3' ends, respectively. We report the identification of mutations in ELAC2 in five individuals with infantile hypertrophic cardiomyopathy and complex I deficiency. We observed accumulated mtRNA precursors in affected individuals muscle and fibroblasts. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation. Complementation experiments in mutant cell lines restored RNA processing and a yeast model provided additional evidence for the disease-causal role of defective ELAC2, thereby linking mtRNA processing to human disease.