Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA-associated pathogenesis which provides evidence for RNA dysfunction.

中文翻译：

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肌苷三磷酸焦磷酸酶：细胞核苷酸库的守护者和 RNA 功能的潜在介质

肌苷三磷酸焦磷酸酶 (ITPase) 由人类 ITPA 基因编码，是一种重要的酶，可将非经典嘌呤核苷酸（脱氧）肌苷和（脱氧）黄苷三磷酸水解为单磷酸和焦磷酸，从而保持细胞核苷酸库的完整性。ITPA中的变体基因可导致部分或完全ITPase缺乏。部分 ITP 酶缺乏是良性的，但具有临床相关性，因为它与药物反应的改变有关。ITP酶完全缺乏会导致严重的多系统疾病，其特征是癫痫和脑病，通常与致命的婴儿扩张型心肌病相关。在缺乏 ITPase 活性的情况下，其底物非规范核苷酸有可能积累并异常掺入 DNA 和 RNA。因此，ITPase 缺乏的病理生理学可能是由代谢失衡、DNA 或 RNA 调节改变或这些因素的组合引起的。在这里，我们回顾了 ITPase 的已知功能，并重点介绍了旨在确定ITPA分子基础的近期工作相关的发病机制为 RNA 功能障碍提供了证据。