通过硅分析实现精氨酸琥珀酸合成酶的可视化:对瓜氨酸血症 I 型疾病的新见解。

IF 3.9 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Frontiers in Molecular Biosciences Pub Date : 2024-11-22 eCollection Date: 2024-01-01 DOI:10.3389/fmolb.2024.1482773
Xia Gu, Wenhui Mo, Guiying Zhuang, Congcong Shi, Tao Wei, Jinze Zhang, Chiaowen Tu, Yao Cai, Biwen Liao, Hu Hao
{"title":"通过硅分析实现精氨酸琥珀酸合成酶的可视化:对瓜氨酸血症 I 型疾病的新见解。","authors":"Xia Gu, Wenhui Mo, Guiying Zhuang, Congcong Shi, Tao Wei, Jinze Zhang, Chiaowen Tu, Yao Cai, Biwen Liao, Hu Hao","doi":"10.3389/fmolb.2024.1482773","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>c.1128_1134delinsG</i> 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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1482773"},"PeriodicalIF":3.9000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621003/pdf/","citationCount":"0","resultStr":"{\"title\":\"Visualization of argininosuccinate synthetase by <i>in silico</i> analysis: novel insights into citrullinemia type I disorders.\",\"authors\":\"Xia Gu, Wenhui Mo, Guiying Zhuang, Congcong Shi, Tao Wei, Jinze Zhang, Chiaowen Tu, Yao Cai, Biwen Liao, Hu Hao\",\"doi\":\"10.3389/fmolb.2024.1482773\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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 <i>c.1128_1134delinsG</i> 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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":12465,\"journal\":{\"name\":\"Frontiers in Molecular Biosciences\",\"volume\":\"11 \",\"pages\":\"1482773\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2024-11-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621003/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in Molecular Biosciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.3389/fmolb.2024.1482773\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Molecular Biosciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3389/fmolb.2024.1482773","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:瓜氨酸血症I型疾病(CTLN1)是由精氨酸琥珀酸合成酶(ASS1)基因突变引起的遗传性代谢性疾病。迄今为止,人类基因组突变数据库已经记录了超过100种ASS1基因变异。本研究报道了一种新的ASS1基因缺失插入变异,并利用各种预测工具确定其致病性。方法:我们报告1例早发性CTLN1。全外显子组测序鉴定基因突变。我们使用各种结构预测工具来生成精确的3D模型,并利用计算生物学工具来阐明野生型和突变型蛋白质之间的差异。结果:患者临床表现严重,包括反应性差、嗜睡、惊厥、心脏骤停等。值得注意的是,患者血氨水平明显升高(655 μmol/L;正常参比:10 ~ 30 μmol/L),瓜氨酸浓度升高(936 μmol/L;标准参比:5 ~ 25 μmol/L)。全外显子组测序显示,ASS1基因框内缺失插入突变c.1128_1134delinsG意义未知,此前未见报道。我们的发现表明,突变蛋白结构的C-末端螺旋结构域确实比野生型蛋白结构更不稳定,这是ASS1蛋白形成蛋白四聚体的重要结构。结论:通过对ASS1独特的帧内缺失插入变体进行计算机分析,我们的目的是加强对其结构-功能关系的理解,并揭示CTLN1的分子机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Visualization of argininosuccinate synthetase by in silico analysis: novel insights into citrullinemia type I disorders.

Background: 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.

Methods: 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.

Results: 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 c.1128_1134delinsG 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.

Conclusion: 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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Frontiers in Molecular Biosciences
Frontiers in Molecular Biosciences Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
7.20
自引率
4.00%
发文量
1361
审稿时长
14 weeks
期刊介绍: Much of contemporary investigation in the life sciences is devoted to the molecular-scale understanding of the relationships between genes and the environment — in particular, dynamic alterations in the levels, modifications, and interactions of cellular effectors, including proteins. Frontiers in Molecular Biosciences offers an international publication platform for basic as well as applied research; we encourage contributions spanning both established and emerging areas of biology. To this end, the journal draws from empirical disciplines such as structural biology, enzymology, biochemistry, and biophysics, capitalizing as well on the technological advancements that have enabled metabolomics and proteomics measurements in massively parallel throughput, and the development of robust and innovative computational biology strategies. We also recognize influences from medicine and technology, welcoming studies in molecular genetics, molecular diagnostics and therapeutics, and nanotechnology. Our ultimate objective is the comprehensive illustration of the molecular mechanisms regulating proteins, nucleic acids, carbohydrates, lipids, and small metabolites in organisms across all branches of life. In addition to interesting new findings, techniques, and applications, Frontiers in Molecular Biosciences will consider new testable hypotheses to inspire different perspectives and stimulate scientific dialogue. The integration of in silico, in vitro, and in vivo approaches will benefit endeavors across all domains of the life sciences.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信