Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden
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 pre...
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| Format: | Article |
| Language: | English |
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Georg Thieme Verlag KG
2023-01-01
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| Series: | TH Open |
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| Online Access: | http://www.thieme-connect.de/DOI/DOI?10.1055/a-1987-5978 |
| _version_ | 1797957199709863936 |
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| author | Christos Efthymiou Emily H.T. Print Anna Simmons Stephen J. Perkins |
| author_facet | Christos Efthymiou Emily H.T. Print Anna Simmons Stephen J. Perkins |
| author_sort | Christos Efthymiou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T00:01:41Z |
| format | Article |
| id | doaj.art-ee42d11dd59d4ae88814df7e16ffd767 |
| institution | Directory Open Access Journal |
| issn | 2512-9465 |
| language | English |
| last_indexed | 2024-04-11T00:01:41Z |
| publishDate | 2023-01-01 |
| publisher | Georg Thieme Verlag KG |
| record_format | Article |
| series | TH Open |
| spelling | doaj.art-ee42d11dd59d4ae88814df7e16ffd7672023-01-10T04:58:12ZengGeorg Thieme Verlag KGTH Open2512-94652023-01-010701e30e4110.1055/a-1987-5978Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV LeidenChristos Efthymiou0Emily H.T. Print1Anna Simmons2Stephen J. Perkins3Research Department of Structural and Molecular Biology, University College London, London, United KingdomResearch Department of Structural and Molecular Biology, University College London, London, United KingdomResearch Department of Structural and Molecular Biology, University College London, London, United KingdomResearch Department of Structural and Molecular Biology, University College London, London, United KingdomThe 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.http://www.thieme-connect.de/DOI/DOI?10.1055/a-1987-5978coagulation factorsprotein structurecoagulationgene mutations |
| spellingShingle | Christos Efthymiou Emily H.T. Print Anna Simmons Stephen J. Perkins Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden TH Open coagulation factors protein structure coagulation gene mutations |
| title | Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden |
| title_full | Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden |
| title_fullStr | Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden |
| title_full_unstemmed | Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden |
| title_short | Analysis of 363 Genetic Variants in F5 via an Interactive Web Database Reveals New Insights into FV Deficiency and FV Leiden |
| title_sort | analysis of 363 genetic variants in f5 via an interactive web database reveals new insights into fv deficiency and fv leiden |
| topic | coagulation factors protein structure coagulation gene mutations |
| url | http://www.thieme-connect.de/DOI/DOI?10.1055/a-1987-5978 |
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