Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.

中文翻译：

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致病性 PDE12 变体损害线粒体 RNA 加工，导致新生儿线粒体疾病。


线粒体或核基因组中的致病性变异与一组以线粒体功能受损为特征的多种人类疾病有关。在该组中，已经确定了越来越多的家庭，其中孟德尔遗传疾病与线粒体 RNA 生物学缺陷有关。PDE12 基因编码 poly （A） 特异性核糖核酸外切酶，参与线粒体非编码 RNA 的质量控制。在这里，我们报道了三个不相关家族中的致病 PDE12 变异与子宫内和新生儿期的线粒体呼吸链缺陷和广泛的临床表现有关，肌肉和大脑受累导致肌肉中明显的细胞色素 c 氧化酶 （COX） 缺乏和严重的乳酸酸中毒。受影响先证者的全外显子组测序揭示了影响保守残基的新型分离双等位基因错义 PDE12 变体。患者来源的原代成纤维细胞显示 PDE12 蛋白的稳态水平降低，而线粒体 poly（A） 尾 RNA 测序 （MPAT-Seq） 显示假性多聚腺苷酸化线粒体 RNA 的积累，与 PDE12 蛋白的功能受扰动一致。我们的数据表明，PDE12 调节线粒体 RNA 加工，其丢失导致神经和肌肉表型。