Department of Human Genetics, and Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Zhejiang University School of Medicine, Hangzhou, China.
Hum Genomics. 2020 Dec 7;14(1):45. doi: 10.1186/s40246-020-00295-z.
Germline variants of ten keratin genes (K1, K2, K5, K6A, K6B, K9, K10, K14, K16, and K17) have been reported for causing different types of genodermatoses with an autosomal dominant mode of inheritance. Among all the variants of these ten keratin genes, most of them are missense variants. Unlike pathogenic and likely pathogenic variants, understanding the clinical importance of novel missense variants or variants of uncertain significance (VUS) is the biggest challenge for clinicians or medical geneticists. Functional characterization is the only way to understand the clinical association of novel missense variants or VUS but it is time consuming, costly, and depends on the availability of patient's samples. Existing databases report the pathogenic variants of the keratin genes, but never emphasize the systematic effects of these variants on keratin protein structure and genotype-phenotype correlation.
To address this need, we developed a comprehensive database KVarPredDB, which contains information of all ten keratin genes associated with genodermatoses. We integrated and curated 400 reported pathogenic missense variants as well as 4629 missense VUS. KVarPredDB predicts the pathogenicity of novel missense variants as well as to understand the severity of disease phenotype, based on four criteria; firstly, the difference in physico-chemical properties between the wild type and substituted amino acids; secondly, the loss of inter/intra-chain interactions; thirdly, evolutionary conservation of the wild type amino acids and lastly, the effect of the substituted amino acids in the heptad repeat. Molecular docking simulations based on resolved crystal structures were adopted to predict stability changes and get the binding energy to compare the wild type protein with the mutated one. We use this basic information to determine the structural and functional impact of novel missense variants on the keratin coiled-coil heterodimer. KVarPredDB was built under the integrative web application development framework SSM (SpringBoot, Spring MVC, MyBatis) and implemented in Java, Bootstrap, React-mutation-mapper, MySQL, Tomcat. The website can be accessed through http://bioinfo.zju.edu.cn/KVarPredDB . The genomic variants and analysis results are freely available under the Creative Commons license.
KVarPredDB provides an intuitive and user-friendly interface with computational analytical investigation for each missense variant of the keratin genes associated with genodermatoses.
已经报道了十个角蛋白基因（K1、K2、K5、K6A、K6B、K9、K10、K14、K16 和 K17）的种系变体，这些变体导致具有常染色体显性遗传模式的不同类型的遗传性皮肤病。在这十个角蛋白基因的所有变体中，大多数是错义变体。与致病性和可能致病性变体不同，理解新型错义变体或意义不确定的变体（VUS）的临床重要性是临床医生或医学遗传学家面临的最大挑战。功能特征分析是了解新型错义变体或 VUS 与临床关联的唯一方法，但它既耗时、昂贵，又依赖于患者样本的可用性。现有的数据库报告了角蛋白基因的致病性变体，但从未强调这些变体对角蛋白蛋白结构和基因型-表型相关性的系统影响。
为了解决这一需求，我们开发了一个综合数据库 KVarPredDB，其中包含与遗传性皮肤病相关的十个角蛋白基因的信息。我们整合并整理了 400 个已报道的致病性错义变体以及 4629 个错义 VUS。KVarPredDB 基于四个标准预测新型错义变体的致病性以及理解疾病表型严重程度，这四个标准分别是：首先，野生型和取代氨基酸之间的理化性质差异；其次，链间/链内相互作用的丧失；第三，野生型氨基酸的进化保守性；最后，取代氨基酸在七肽重复中的作用。采用基于已解析晶体结构的分子对接模拟来预测稳定性变化并获得结合能，以比较野生型蛋白和突变型蛋白。我们使用这些基本信息来确定新型错义变体对角蛋白卷曲螺旋异二聚体的结构和功能影响。KVarPredDB 是在集成的 Web 应用程序开发框架 SSM（SpringBoot、Spring MVC、MyBatis）下构建的，并使用 Java、Bootstrap、React-mutation-mapper、MySQL 和 Tomcat 实现。可以通过 http://bioinfo.zju.edu.cn/KVarPredDB 访问该网站。基因组变体和分析结果可在知识共享许可下免费获得。
KVarPredDB 为与遗传性皮肤病相关的角蛋白基因的每个错义变体提供了一个直观且用户友好的界面，并进行了计算分析研究。
