Efthymiou, Christos;
Print, Emily HT;
Simmons, Anna;
Perkins, Stephen J;
(2022)
Analysis of 363 variants in the coagulation Factor 5 gene via an interactive web database reveals new insights into FV deficiency and FV Leiden.
TH Open
10.1055/a-1987-5978.
(In press).
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Abstract
The inherited bleeding disorder FV deficiency and clotting disorder FV Leiden are caused by genetic variants in the F5 gene. Both diseases occur 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 disease-associated unique F5 variants derived from 801 patient records that rationalizes their occurrence based on the 2224 residue sequence and new FV structures. The 363 variants correspond to 38 (10.5%) mild, 14 (3.9%) moderate, 52 (14.3%) severe, 49 (13.5%) asymptomatic, and 210 (57.8%) unreported phenotypes. The variant distribution in the FV domains A1, A2, A3, B, C1 and C2 was 42 (11.9%), 61 (17.2%), 58 (16.4%), 103 (29.1%), 28 (7.9%) and 29 variants (8.2%) respectively. Both the globular (A1-A3, C1, C2) and disordered (B) regions contain similar proportions of variants. Variants associated with either FV deficiency or FV Leiden do not cluster near known protein-partner binding sites, thus the molecular mechanism leading to their 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-associated disorders.
| Type: | Article |
|---|---|
| Title: | Analysis of 363 variants in the coagulation Factor 5 gene via an interactive web database reveals new insights into FV deficiency and FV Leiden |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1055/a-1987-5978 |
| Publisher version: | https://doi.org/10.1055/a-1987-5978 |
| Language: | English |
| Additional information: | © 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/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10161541 |
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