VarMeter: a prediction method for the impact of glycogene variants.

IF 2.5 3区 生物学 Q2 GENETICS & HEREDITY
Shiho Ohno, Noriyoshi Manabe, Tadashi Kaname, Shoko Nishihara, Yoshiki Yamaguchi
{"title":"VarMeter: a prediction method for the impact of glycogene variants.","authors":"Shiho Ohno, Noriyoshi Manabe, Tadashi Kaname, Shoko Nishihara, Yoshiki Yamaguchi","doi":"10.1038/s10038-025-01364-8","DOIUrl":null,"url":null,"abstract":"<p><p>The clinical relevance of glycans, which play a wide array of physiological roles, is underscored by the emergence of congenital disorders of glycosylation, a group of rare inherited diseases caused by defects in glycan-related genes (glycogenes). Biochemical studies of recombinant proteins and phenotypic analyses in knockout mice are revealing critical insights into the roles of various glycosyltransferases, glycosidases, and glycan-binding proteins. However, the biological functions of numerous glycogenes and their role in disease remain incompletely understood, partly due to human-specific functions that are not recapitulated in model organisms, and partly due to the structural diversity and complexity of glycan modifications, which are difficult to fully assess by conventional methods. A promising complementary strategy is the systematic assessment of human genetic variants, particularly missense mutations, to infer functional consequences. Recent developments in protein structure prediction, exemplified by AlphaFold, are facilitating the development of structure-based approaches to variant interpretation. In this review, we discuss current methodologies for predicting the impact of missense variants using structural information, and introduce VarMeter, a computational framework incorporating 3D structural parameters that has been successfully applied to the prediction of pathogenic variants in the ClinVar database. We also describe VarMeter2, an updated version that integrates AlphaFold-derived pLDDT confidence scores and Mahalanobis distance analysis to improve prediction accuracy, demonstrating its ability to predict pathogenic variants of four glycan-related proteins. These tools offer a novel avenue for uncovering previously unrecognized functions of glycogenes and their links to disease, and contribute to the clinical interpretation of genetic variation.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5000,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Human Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s10038-025-01364-8","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

The clinical relevance of glycans, which play a wide array of physiological roles, is underscored by the emergence of congenital disorders of glycosylation, a group of rare inherited diseases caused by defects in glycan-related genes (glycogenes). Biochemical studies of recombinant proteins and phenotypic analyses in knockout mice are revealing critical insights into the roles of various glycosyltransferases, glycosidases, and glycan-binding proteins. However, the biological functions of numerous glycogenes and their role in disease remain incompletely understood, partly due to human-specific functions that are not recapitulated in model organisms, and partly due to the structural diversity and complexity of glycan modifications, which are difficult to fully assess by conventional methods. A promising complementary strategy is the systematic assessment of human genetic variants, particularly missense mutations, to infer functional consequences. Recent developments in protein structure prediction, exemplified by AlphaFold, are facilitating the development of structure-based approaches to variant interpretation. In this review, we discuss current methodologies for predicting the impact of missense variants using structural information, and introduce VarMeter, a computational framework incorporating 3D structural parameters that has been successfully applied to the prediction of pathogenic variants in the ClinVar database. We also describe VarMeter2, an updated version that integrates AlphaFold-derived pLDDT confidence scores and Mahalanobis distance analysis to improve prediction accuracy, demonstrating its ability to predict pathogenic variants of four glycan-related proteins. These tools offer a novel avenue for uncovering previously unrecognized functions of glycogenes and their links to disease, and contribute to the clinical interpretation of genetic variation.

变量计:预测糖基因变异影响的方法。
糖基化先天性疾病是一组由糖基相关基因(糖基因)缺陷引起的罕见遗传性疾病,它的出现强调了糖基化的临床意义,它具有广泛的生理作用。重组蛋白的生化研究和基因敲除小鼠的表型分析揭示了各种糖基转移酶、糖苷酶和聚糖结合蛋白的重要作用。然而,许多糖原的生物学功能及其在疾病中的作用仍然不完全清楚,部分原因是人类特有的功能在模式生物中没有得到概括,部分原因是聚糖修饰的结构多样性和复杂性,难以用常规方法充分评估。一个有希望的补充策略是系统地评估人类遗传变异,特别是错义突变,以推断功能后果。以AlphaFold为例,蛋白质结构预测的最新发展正在促进基于结构的变异解释方法的发展。在这篇综述中,我们讨论了目前使用结构信息预测错义变异影响的方法,并介绍了VarMeter,这是一个包含3D结构参数的计算框架,已成功应用于预测ClinVar数据库中的致病变异。我们还描述了VarMeter2,这是一个集成了alphafold衍生的pLDDT置信度评分和马氏距离分析以提高预测准确性的更新版本,证明了其预测四种聚糖相关蛋白的致病变异的能力。这些工具为揭示以前未被认识到的糖基因功能及其与疾病的联系提供了新的途径,并有助于遗传变异的临床解释。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Journal of Human Genetics
Journal of Human Genetics 生物-遗传学
CiteScore
7.20
自引率
0.00%
发文量
101
审稿时长
4-8 weeks
期刊介绍: The Journal of Human Genetics is an international journal publishing articles on human genetics, including medical genetics and human genome analysis. It covers all aspects of human genetics, including molecular genetics, clinical genetics, behavioral genetics, immunogenetics, pharmacogenomics, population genetics, functional genomics, epigenetics, genetic counseling and gene therapy. Articles on the following areas are especially welcome: genetic factors of monogenic and complex disorders, genome-wide association studies, genetic epidemiology, cancer genetics, personal genomics, genotype-phenotype relationships and genome diversity.
×
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:604180095
Book学术官方微信