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CC BY 4.0 · TH Open 2023; 07(01): e30-e41
DOI: 10.1055/a-1987-5978
Original Article

Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden

Christos Efthymiou 
1   Research Department of Structural and Molecular Biology, University College London, London, United Kingdom
,
Emily H.T. Print 
1   Research Department of Structural and Molecular Biology, University College London, London, United Kingdom
,
Anna Simmons 
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

The inherited bleeding disorder Factor V (FV) deficiency and clotting risk factor FV Leiden are associated with genetic variants in the F5 gene. FV deficiency occurs with mild, moderate, severe, or asymptomatic phenotypes, and either dysfunctional or reduced amounts of plasma FV protein. Here we present an interactive web database containing 363 unique F5 variants derived from 801 patient records, with 199 FV deficiency-associated variants from 245 patient records. Their occurrence is rationalized based on the 2,224 residue sequence and new FV protein structures. The 199 FV deficiency variants correspond to 26 (13%) mild, 22 (11%) moderate, 49 (25%) severe, 35 (18%) asymptomatic, and 67 (34%) unreported phenotypes. Their variant distributions in the FV domains A1, A2, A3, B, C1 and C2 were 28 (14%), 32 (16%), 34 (17%), 42 (21%), 16 (8%), and 19 variants (10%), respectively, showing that these six regions contain similar proportions of variants. Variants associated with FV deficiency do not cluster near known protein-partner binding sites, thus the molecular mechanism leading to the phenotypes cannot be explained. However, the widespread distribution of FV variants in combination with a high proportion of buried variant residues indicated that FV is susceptible to disruption by small perturbations in its globular structure. Variants located in the disordered B domain also appear to disrupt the FV structure. We discuss how the interactive database provides an online resource that clarifies the clinical understanding of FV deficiency.

Keywords

coagulation factors - protein structure - coagulation - gene mutations

Note

The FV website is available at http://www.factorv-db.org.


Supplementary Material



Publikationsverlauf

Eingereicht: 19. August 2022

Angenommen: 11. November 2022

Accepted Manuscript online:
25. November 2022

Artikel online veröffentlicht:
09. Januar 2023

© 2023. 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/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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