Gu Xia, Mo Wenhui, Zhuang Guiying, Shi Congcong, Wei Tao, Zhang Jinze, Tu Chiaowen, Cai Yao, Liao Biwen, Hao Hu
Department of Neonatology, The Sixth Affiliated Hospital, Sun-Yat-Sen University, Guangzhou, China.
Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Front Mol Biosci. 2024 Nov 22;11:1482773. doi: 10.3389/fmolb.2024.1482773. eCollection 2024.
Citrullinemia type I disorders (CTLN1) is a genetic metabolic disease caused by argininosuccinate synthetase (ASS1) gene mutation. To date, the human genome mutation database has documented over 100 variants of the ASS1 gene. This study reported a novel deletion-insertion variant of ASS1 gene and employed various prediction tools to determine its pathogenicity.
We reported a case of early-onset CTLN1. Whole exome sequencing was conducted to identify genetic mutations. We employed various structure prediction tools to generate accurate 3D models and utilized computational biology tools to elucidate the disparities between the wild-type and mutant proteins.
The patient was characterized by severe clinical manifestations, including poor responsiveness, lethargy, convulsions, and cardiac arrest. Notably, the patient exhibited significantly elevated blood ammonia levels (655 μmol/L; normal reference: 10-30 μmol/L) and increased citrulline concentrations (936 μmol/L; normal reference: 5-25 μmol/L). Whole exome sequencing revealed a in-frame deletion-insertion mutation in the ASS1 gene of unknown significance, which has not been previously reported. Our finding indicated that the C- terminal helix domain of the mutant protein structure, which was an important structure for ASS1 protein to form protein tetramers, was indeed more unstable than that of the wild-type protein structure.
Through conducting an in silico analysis on this unique in-frame deletion-insertion variant of ASS1, our aim was to enhance understanding regarding its structure-function relationship as well as unraveling the molecular mechanism underlying CTLN1.
I型瓜氨酸血症（CTLN1）是一种由精氨琥珀酸合成酶（ASS1）基因突变引起的遗传性代谢疾病。迄今为止，人类基因组突变数据库已记录了超过100种ASS1基因变体。本研究报告了一种新的ASS1基因缺失插入变体，并使用多种预测工具来确定其致病性。
我们报告了一例早发型CTLN1病例。进行全外显子组测序以鉴定基因突变。我们使用各种结构预测工具生成准确的三维模型，并利用计算生物学工具阐明野生型和突变型蛋白质之间的差异。
该患者具有严重的临床表现，包括反应迟钝、嗜睡、惊厥和心脏骤停。值得注意的是，患者血氨水平显著升高（655μmol/L；正常参考值：10 - 30μmol/L），瓜氨酸浓度增加（936μmol/L；正常参考值：5 - 25μmol/L）。全外显子组测序揭示了ASS1基因中一个意义不明的框内缺失插入突变，此前尚未见报道。我们的研究结果表明，突变型蛋白质结构的C末端螺旋结构域，这是ASS1蛋白形成蛋白四聚体的重要结构，确实比野生型蛋白质结构更不稳定。
通过对ASS1这种独特的框内缺失插入变体进行计算机分析，我们的目的是增进对其结构 - 功能关系的理解，并揭示CTLN1潜在的分子机制。
