Harris Victoria A, Lin Weining, Perkins Stephen J
Research Department of Structural and Molecular Biology, University College London, London, United Kingdom.
TH Open. 2021 Nov 1;5(4):e543-e556. doi: 10.1055/a-1683-8605. eCollection 2021 Oct.
Coagulation Factor XI (FXI) is a plasma glycoprotein composed of four apple (Ap) domains and a serine protease (SP) domain. FXI circulates as a dimer and activates Factor IX (FIX), promoting thrombin production and preventing excess blood loss. Genetic variants that degrade FXI structure and function often lead to bleeding diatheses, commonly termed FXI deficiency. The first interactive FXI variant database underwent initial development in 2003 at https://www.factorxi.org . Here, based on a much improved FXI crystal structure, the upgraded FXI database contains information regarding 272 FXI variants (including 154 missense variants) found in 657 patients, this being a significant increase from the 183 variants identified in the 2009 update. Type I variants involve the simultaneous reduction of FXI coagulant activity (FXI:C) and FXI antigen levels (FXI:Ag), whereas Type II variants result in decreased FXI:C yet normal FXI:Ag. The database updates now highlight the predominance of Type I variants in FXI. Analysis in terms of a consensus Ap domain revealed the near-uniform distribution of 81 missense variants across the Ap domains. A further 66 missense variants were identified in the SP domain, showing that all regions of the FXI protein were important for function. The variants clarified the critical importance of changes in surface solvent accessibility, as well as those of cysteine residues and the dimer interface. Guidelines are provided below for clinicians who wish to use the database for diagnostic purposes. In conclusion, the updated database provides an easy-to-use web resource on FXI deficiency for clinicians.
凝血因子XI（FXI）是一种血浆糖蛋白，由四个苹果（Ap）结构域和一个丝氨酸蛋白酶（SP）结构域组成。FXI以二聚体形式循环，激活因子IX（FIX），促进凝血酶生成并防止过度失血。破坏FXI结构和功能的基因变异通常会导致出血性疾病，通常称为FXI缺乏症。第一个交互式FXI变异数据库于2003年在https://www.factorxi.org上初步开发。在此，基于大大改进的FXI晶体结构，升级后的FXI数据库包含了在657名患者中发现的272种FXI变异（包括154种错义变异）的信息，这比2009年更新中确定的183种变异有了显著增加。I型变异涉及FXI凝血活性（FXI:C）和FXI抗原水平（FXI:Ag）同时降低，而II型变异导致FXI:C降低但FXI:Ag正常。数据库更新现在突出了I型变异在FXI中的优势。根据一致的Ap结构域进行分析，发现81种错义变异在Ap结构域中分布几乎均匀。在SP结构域中又鉴定出66种错义变异，表明FXI蛋白的所有区域对功能都很重要。这些变异阐明了表面溶剂可及性变化、半胱氨酸残基和二聚体界面变化的关键重要性。以下为希望将该数据库用于诊断目的的临床医生提供指南。总之，更新后的数据库为临床医生提供了一个关于FXI缺乏症的易于使用的网络资源。
