NUDT2 loss-of-function variants are associated with a recessive neurodevelopmental disease with mental retardation, movement disorder and peripheral neuropathy

We present cases of a neurological disorder in children characterized by developmental delays in mental and motor skills, gait disturbances, and peripheral neuropathy. The disorder is associated with rare variants in the NUDT2 gene, which encodes a Nudix family mRNA decapping enzyme. The spectrum of variants includes two previously reported truncating variants and two novel variants, namely the missense c.174G>T and the in-frame deletion c.410_412del. We report that these new variants result in a marked reduction in enzymatic hydrolase activity of the encoded protein, strongly suggesting loss of function of NUDT2 as the cause of the disorder. Morover, we document that loss of function may be due to reduced enzymatic activity or impaired protein stability of NUDT2 variants. Consistent with its function in mRNA decapping, NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, likely due at least in part to changes in mRNA stability. Our results confirm that a reduction or loss of NUDT2-dependent mRNA decapping activity is associated with recessive neurological disease in pediatric patients. Taken together, these findings underscore the importance of a physiologically balanced mRNA processing for neuronal development and homeostasis. Overall design: RNA-Seq was used to identify results of Nudt2 mutations found in patient fibroblasts

本研究报道了一组儿童神经系统疾病病例，该病以精神与运动技能发育迟缓、步态障碍及周围神经病为特征。该疾病与NUDT2基因（NUDT2 gene）的罕见变异相关，该基因编码一种Nudix家族信使RNA（messenger RNA，mRNA）脱帽酶。该类变异谱包含2种此前已报道的截短变异，以及2种新型变异：分别为错义变异c.174G>T及框内缺失变异c.410_412del。本研究发现，上述新型变异可导致编码蛋白的酶水解活性显著降低，强烈提示NUDT2功能丧失是该疾病的致病机制。此外，本研究证实，NUDT2变异的功能丧失可能源于酶活性降低或蛋白稳定性受损。鉴于其在mRNA脱帽过程中的功能，NUDT2缺陷患者的成纤维细胞表现出显著改变的转录组，该改变至少部分源于mRNA稳定性的变化。本研究结果证实，依赖NUDT2的mRNA脱帽活性降低或丧失，与儿科患者的隐性遗传性神经系统疾病相关。综上，上述研究结果强调了生理状态下mRNA加工过程的动态平衡对神经元发育及内环境稳态的重要性。实验整体设计：通过RNA测序（RNA-Seq）分析患者成纤维细胞中Nudt2突变的相关表达结果。