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

Victoria A Harris,Weining Lin,Stephen J Perkins

doi:10.1055/a-1683-8605

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.

Highlights

Factor XI (FXI), a coagulation serine protease, is encoded by the F11 gene located on the long arm of human chromosome 4 (4q35)
Allelic frequencies (AF) are provided for variants when possible using the data supplied by the genome aggregation database version 2.1.1
Deficiency, and disease severity, it is unlikely that the updated FXI database will provide a clear answer to this conundrum

Summary

Introduction

Factor XI (FXI), a coagulation serine protease, is encoded by the F11 gene located on the long arm of human chromosome 4 (4q35). The 23 kb gene comprises 15 exons that translate into a signal peptide, four apple (Ap) domains (Ap1-Ap4) and the catalytic serine protease (SP) domain (Figure 1).[1,2] The Ap domains in FXI are structurally homologous to each other and to those in human prekallikrein (PK), a zymogen protease involved in the kallikrein-kinin-system (KKS). Together such Ap domains form part of the plasminogenapple-nematode (PAN) domain superfamily.[3] FXI appeared to arise from the duplication of the PK gene, Klkb[1], making FXI and PK paralogs of each other.

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