Argininosuccinate lyase (ASL) deficiency impairs the function of the urea cycle that detoxifies blood ammonia in the body. Mutation that occurs in the ASL gene is the cause of occurrence of ASL deficiency (ASLD). This deficiency causes hyperammonemia, hepatopathy and neurodevelopmental delay in patients. In this study, the clinical characteristics and molecular analysis of 10 ASLD patients were presented. 8 patients were associated with severe neonatal onset, while the other 2 were associated with late onset. Molecular analysis of ASL gene identified four new missense variants, which were c.778C>T, p.(Leu260Arg), c.1340G>C, p.(Ser447Thr), c.436C>G, p.(Arg146Gly) and c.595C>G, p.(Leu199Val) and four reported missense variants, which were c.638G>A, p.(Arg213Gln); c.556C>T, p.(Arg186Trp), c.578G>A, p.(Arg193Gln) and c.436C>G, p.(Arg146Trp). In silico servers predicted all new and reported variants as disease-causing. Structural examination exhibited that all pathogenic variants affected the stability of the tetrameric ASL structure by disturbing the bonding pattern with the neighboring residues.

Conclusion

This study revealed the genetic heterogeneity among Malaysian ASL patients. This study has also expanded the mutational spectrum of the ASL.

中文翻译：

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马来西亚精氨酸琥珀酸裂解酶 (ASL) 缺乏症患者的突变鉴定。

精氨琥珀酸裂解酶 (ASL) 缺乏会损害体内血氨解毒的尿素循环功能。ASL基因中发生的突变是导致 ASL 缺陷 (ASLD) 发生的原因。这种缺乏会导致患者出现高氨血症、肝病和神经发育迟缓。在这项研究中，介绍了 10 例 ASLD 患者的临床特征和分子分析。8例与重度新生儿发病有关，另外2例与迟发有关。ASL的分子分析基因鉴定出四种新的错义变异，分别是c.778C>T、p.(Leu260Arg)、c.1340G>C、p.(Ser447Thr)、c.436C>G、p.(Arg146Gly)和c.595C>G , p.(Leu199Val) 和四个报告的错义变体, 它们是 c.638G>A, p.(Arg213Gln); c.556C>T, p.(Arg186Trp), c.578G>A, p.(Arg193Gln) 和 c.436C>G, p.(Arg146Trp)。在计算机上，服务器预测所有新的和报告的变体都是致病的。结构检查表明，所有致病变异都通过扰乱与相邻残基的结合模式来影响四聚体 ASL 结构的稳定性。

结论

这项研究揭示了马来西亚 ASL 患者的遗传异质性。这项研究还扩大了 ASL 的突变谱。