{"title":"用计算机方法评价神经管缺陷相关错义突变的功能","authors":"Burcu Biterge Sut","doi":"10.1002/bdr2.2453","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Neural tube formation is one of the most important developmental events as it gives rise to the key organs comprising the central nervous system. Failure in the proper closure of the neural tube results in congenital abnormalities, namely neural tube defects (NTDs). Previous studies have identified several single nucleotide variations that are considered risk factors and established a genetic background for the increased incidence of NTDs and factors. This study aims to provide a comprehensive functional analysis of NTD-related missense mutations in terms of their potential effects on pathogenicity, protein stability, and structure using predictive in silico analysis tools.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Single nucleotide variations associated with NTD risk were identified by a systematic review of previous studies on Pubmed and ClinVar. Protein stability and pathogenicity scores were predicted using MUpro and PloyPhen2, respectively. Structural alterations were determined via the HOPE server. Predicted expression profiles in the brain were retrieved from the Human Protein Atlas.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Our analysis identified 43 NTD-related missense mutations in MTHFR, MTRR, PARD3, PACS1, MED12, VANGL1, VANGL2, FZD6, CELSR1, FUZ, DVL2, and LRP6 genes. We found that all of these genes are predicted to be expressed in different regions of the brain. We showed that single nucleotide variations resulted in decreased protein stability, and the majority of them were found to be damaging. We also report that the amino acid changes introduced by these mutations caused differences in size, charge, and hydrophobicity, which potentially resulted in structural alterations within the protein and affected their contacts with other proteins and ligands.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>In conclusion, this study provides a comprehensive analysis of NTD-related missense mutations regarding their potential damaging effects, which might contribute to the pathogenesis of NTDs.</p>\n </section>\n </div>","PeriodicalId":9121,"journal":{"name":"Birth Defects Research","volume":"117 2","pages":""},"PeriodicalIF":1.6000,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Functional Evaluation of Neural Tube Defect-Related Missense Mutations Using In Silico Methods\",\"authors\":\"Burcu Biterge Sut\",\"doi\":\"10.1002/bdr2.2453\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Neural tube formation is one of the most important developmental events as it gives rise to the key organs comprising the central nervous system. Failure in the proper closure of the neural tube results in congenital abnormalities, namely neural tube defects (NTDs). Previous studies have identified several single nucleotide variations that are considered risk factors and established a genetic background for the increased incidence of NTDs and factors. This study aims to provide a comprehensive functional analysis of NTD-related missense mutations in terms of their potential effects on pathogenicity, protein stability, and structure using predictive in silico analysis tools.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Single nucleotide variations associated with NTD risk were identified by a systematic review of previous studies on Pubmed and ClinVar. Protein stability and pathogenicity scores were predicted using MUpro and PloyPhen2, respectively. Structural alterations were determined via the HOPE server. Predicted expression profiles in the brain were retrieved from the Human Protein Atlas.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Our analysis identified 43 NTD-related missense mutations in MTHFR, MTRR, PARD3, PACS1, MED12, VANGL1, VANGL2, FZD6, CELSR1, FUZ, DVL2, and LRP6 genes. We found that all of these genes are predicted to be expressed in different regions of the brain. We showed that single nucleotide variations resulted in decreased protein stability, and the majority of them were found to be damaging. We also report that the amino acid changes introduced by these mutations caused differences in size, charge, and hydrophobicity, which potentially resulted in structural alterations within the protein and affected their contacts with other proteins and ligands.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>In conclusion, this study provides a comprehensive analysis of NTD-related missense mutations regarding their potential damaging effects, which might contribute to the pathogenesis of NTDs.</p>\\n </section>\\n </div>\",\"PeriodicalId\":9121,\"journal\":{\"name\":\"Birth Defects Research\",\"volume\":\"117 2\",\"pages\":\"\"},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2025-02-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Birth Defects Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/bdr2.2453\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"DEVELOPMENTAL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Birth Defects Research","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/bdr2.2453","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"DEVELOPMENTAL BIOLOGY","Score":null,"Total":0}
Functional Evaluation of Neural Tube Defect-Related Missense Mutations Using In Silico Methods
Background
Neural tube formation is one of the most important developmental events as it gives rise to the key organs comprising the central nervous system. Failure in the proper closure of the neural tube results in congenital abnormalities, namely neural tube defects (NTDs). Previous studies have identified several single nucleotide variations that are considered risk factors and established a genetic background for the increased incidence of NTDs and factors. This study aims to provide a comprehensive functional analysis of NTD-related missense mutations in terms of their potential effects on pathogenicity, protein stability, and structure using predictive in silico analysis tools.
Methods
Single nucleotide variations associated with NTD risk were identified by a systematic review of previous studies on Pubmed and ClinVar. Protein stability and pathogenicity scores were predicted using MUpro and PloyPhen2, respectively. Structural alterations were determined via the HOPE server. Predicted expression profiles in the brain were retrieved from the Human Protein Atlas.
Results
Our analysis identified 43 NTD-related missense mutations in MTHFR, MTRR, PARD3, PACS1, MED12, VANGL1, VANGL2, FZD6, CELSR1, FUZ, DVL2, and LRP6 genes. We found that all of these genes are predicted to be expressed in different regions of the brain. We showed that single nucleotide variations resulted in decreased protein stability, and the majority of them were found to be damaging. We also report that the amino acid changes introduced by these mutations caused differences in size, charge, and hydrophobicity, which potentially resulted in structural alterations within the protein and affected their contacts with other proteins and ligands.
Conclusions
In conclusion, this study provides a comprehensive analysis of NTD-related missense mutations regarding their potential damaging effects, which might contribute to the pathogenesis of NTDs.
期刊介绍：
The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks.
Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.
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