Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies.
Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies.
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DOI：
10.1016/j.ajhg.2016.03.010
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发表时间：
2016-05-05
影响因子：
9.8
通讯作者：
Taylor RW
中科院分区：
文献类型：
--
作者：
Metodiev MD;Thompson K;Alston CL;Morris AAM;He L;Assouline Z;Rio M;Bahi-Buisson N;Pyle A;Griffin H;Siira S;Filipovska A;Munnich A;Chinnery PF;McFarland R;Rötig A;Taylor RW
线粒体病症在临床上和遗传上是多样的，其中线粒体或核基因中的突变能够引起线粒体基因表达的缺陷。最近，已确定编码参与mt-tRNA加工的因子的几个基因的突变引起线粒体疾病。使用全外显子组测序，我们确定了TRMT 10 C（编码线粒体RNase P蛋白1 [MRPP 1]）的突变，在两个不相关的个体中，他们出生时出现乳酸酸中毒，肌张力减退，喂养困难和耳聋。两人均在呼吸衰竭后5个月死亡。MRPP 1与MRPP 2和MRPP 3沿着形成线粒体核糖核酸酶P（mt-RNase P）复合物，其从多顺反子前体转录物切割mt-tRNA的5′末端。此外，MRPP 1和MRPP 2的稳定复合物具有m1 R9甲基转移酶活性，其在位置9处甲基化mt-tRNA，并且对于将mt-tRNA折叠成其正确的三级结构至关重要。对携带TRMT 10 C错义变体的受影响个体的成纤维细胞的分析显示，MRPP 1蛋白水平降低，mt-RNA前体增加，表明mt-RNA加工受损和线粒体蛋白合成缺陷。通过慢病毒转导野生型TRMT 10 C后对mt-RNA加工和线粒体蛋白合成缺陷的功能性拯救，验证了检测到的变体-受试者1中复合杂合c.542G> T（p.Arg181Leu）和c.814A>G（p.Thr272Ala）变化以及受试者2中纯合c.542G>T（p.Arg181Leu）变体的致病性。我们的研究表明，这些变异影响MRPP 1蛋白的稳定性和mt-tRNA加工，而不影响m1 R9甲基转移酶活性，确定TRMT 10 C突变是线粒体疾病的原因，并强调了RNA加工对正确线粒体功能的重要性。
Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness. Both individuals died at 5 months after respiratory failure. MRPP1, along with MRPP2 and MRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5′ ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m1R9 methyltransferase activity, which methylates mt-tRNAs at position 9 and is vital for folding mt-tRNAs into their correct tertiary structures. Analyses of fibroblasts from affected individuals harboring TRMT10C missense variants revealed decreased protein levels of MRPP1 and an increase in mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis. The pathogenicity of the detected variants—compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) changes in subject 1 and a homozygous c.542G>T (p.Arg181Leu) variant in subject 2—was validated by the functional rescue of mt-RNA processing and mitochondrial protein synthesis defects after lentiviral transduction of wild-type TRMT10C. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m1R9 methyltransferase activity, identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function.