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.

人类线粒体 RNase P (mt-RNase P) 负责线粒体前体 tRNA 的 5' 末端加工，这是线粒体 RNA 成熟的重要步骤，由三个蛋白质亚基组成：TRMT10C、SDR5C1 (HSD10) 和 PRORP。TRMT10C和SDR5C1中的致病变异与不同的隐性或 x 连锁婴儿发病疾病相关，这是由线粒体 RNA 加工缺陷引起的。我们报告了四个与PRORP 中双等位基因变异相关的多系统疾病的无关家族，mt-RNase P 的金属核酸酶亚基。受影响的个体表现出不同的表型，包括感音神经性听力损失、原发性卵巢功能不全、发育迟缓和脑白质变化。来自两个家族中受影响个体的成纤维细胞表明 PRORP 的稳态水平降低，未加工的线粒体转录物的积累，以及线粒体编码蛋白的稳态水平降低，这些蛋白通过引入野生型 PRORP cDNA 得以挽救。在使用重组 mt-RNase P 蛋白进行的 mt-tRNA 加工分析中，疾病相关变异导致线粒体 tRNA 加工减少。鉴定PRORP 中的致病变异 表明 mt-RNase P 的所有三个亚基中的致病变异可导致线粒体功能障碍，每种都有不同的多效性临床表现。