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CC BY 4.0 · TH Open 2021; 05(04): e543-e556
DOI: 10.1055/a-1683-8605
Original Article

Analysis of 272 Genetic Variants in the Upgraded Interactive FXI Web Database Reveals New Insights into FXI Deficiency

Victoria A. Harris
1   Research Department of Structural and Molecular Biology, University College London, London, United Kingdom
,
Weining Lin
1   Research Department of Structural and Molecular Biology, University College London, London, United Kingdom
,
Stephen J. Perkins 
1   Research Department of Structural and Molecular Biology, University College London, London, United Kingdom
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Abstract

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.

Keywords

coagulation factors - haemostasis - protein structure/folding - inherited coagulation disorders - gene mutations

Research Grants and Financial Support

The authors were supported by grants from the Lister Institute for Preventive Medicine for this work.




Publication History

Received: 04 May 2021

Accepted: 27 October 2021

Accepted Manuscript online:
01 November 2021

Article published online:
17 January 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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