Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations.
Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations.
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DOI：
10.1016/j.ajhg.2021.10.002
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发表时间：
2021-11-04
影响因子：
9.8
通讯作者：
Newman WG
中科院分区：
文献类型：
--
作者：
Hochberg I;Demain LAM;Richer J;Thompson K;Urquhart JE;Rea A;Pagarkar W;Rodríguez-Palmero A;Schlüter A;Verdura E;Pujol A;Quijada-Fraile P;Amberger A;Deutschmann AJ;Demetz S;Gillespie M;Belyantseva IA;McMillan HJ;Barzik M;Beaman GM;Motha R;Ng KY;O'Sullivan J;Williams SG;Bhaskar SS;Lawrence IR;Jenkinson EM;Zambonin JL;Blumenfeld Z;Yalonetsky S;Oerum S;Rossmanith W;Genomics England Research Consortium;Yue WW;Zschocke J;Munro KJ;Battersby BJ;Friedman TB;Taylor RW;O'Keefe RT;Newman WG
人线粒体RNase P(mt-RNase P)负责线粒体前体tRNAs的5‘端加工，是线粒体RNA成熟的关键步骤，由三个蛋白质亚基组成：TRMT10C、SDR5C1(HSD10)和PRORP。TRMT10C和SDR5C1的致病变异与不同的隐性或x连锁婴儿发病障碍有关，这些疾病是由线粒体RNA加工缺陷引起的。我们报告了四个与PRORP(mt-RNaseP的金属核酸酶亚基)双等位基因变异相关的多系统疾病的无关家系。受影响的个体表现出不同的表型，包括感觉神经性听力损失、原发卵巢功能不全、发育迟缓和脑白质改变。来自两个家系的受影响个体的成纤维细胞显示，PRORP的稳态水平降低，未处理的线粒体转录本积累，线粒体编码蛋白的稳态水平降低，这可以通过引入野生型PRORP基因来挽救。在用重组mt-RNaseP蛋白进行的mt-tRNA加工分析中，与疾病相关的变异导致线粒体tRNA加工减少。对PRORP致病变异的鉴定表明，mt-RNaseP的所有三个亚基上的致病变异都可以导致线粒体功能障碍，每个亚基都有不同的多效性临床表现。
Human mitochondrial RNase P (mt-RNase P) is responsible for 5′ end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.
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影响因子：
14.9
作者：
Vilardo E;Nachbagauer C;Buzet A;Taschner A;Holzmann J;Rossmanith W
通讯作者：
Rossmanith W
影响因子：
3.5
作者：
Deutschmann, Andrea J.;Amberger, Albert;Zschocke, Johannes
通讯作者：
Zschocke, Johannes
影响因子：
3.7
作者：
Rossmanith W
通讯作者：
Rossmanith W
影响因子：
2.4
作者：
Delgado, Thomas;Petralia, Ronald S.;Yao, Pamela J.
通讯作者：
Yao, Pamela J.
影响因子：
64.8
作者：
OJALA, D;MONTOYA, J;ATTARDI, G
通讯作者：
ATTARDI, G