RSS-Feed abonnieren
![](/products/assets/desktop/img/oa-logo.png)
DOI: 10.1055/a-1704-0841
Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency
![](https://www.thieme-connect.de/media/10.1055-s-00033990/202104/lookinside/thumbnails/10-1055-a-1704-0841_210055-1.jpg)
Abstract
Coagulation factor X (FX), often termed as Stuart–Prower factor, is a plasma glycoprotein composed of the γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor domains (EGF-1 and EGF-2), and the serine protease (SP) domain. FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in FX disrupt coagulation and lead to FX or Stuart–Prower factor deficiency. To better understand the relationship between FX deficiency and disease severity, an interactive FX variant database has been set up at https://www.factorx-db.org , based on earlier web sites for the factor-XI and -IX coagulation proteins. To date (April 2021), we report 427 case reports on FX deficiency corresponding to 180 distinct F10 genetic variants. Of these, 149 are point variants (of which 128 are missense), 22 are deletions, 3 are insertions, and 6 are polymorphisms. FX variants are phenotypically classified as being type I or II. Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels. Both types of variants were distributed throughout the FXa protein structure. Analyses based on residue surface accessibilities showed the most damaging variants to occur at residues with low accessibilities. The interactive FX web database provides a novel easy-to-use resource for clinicians and scientists to improve the understanding of FX deficiency. Guidelines are provided for clinicians who wish to use the database for diagnostic purposes.
Keywords
coagulation factors - hemostasis - protein structure/folding - gene mutations - inherited coagulation disordersResearch Grants and Financial Support
The authors V.A.H. and W.L. were supported by studentships from the Lister Institute of Preventive Medicine for this project. The authors declare that they have no conflicts of interest with this research.
Publikationsverlauf
Eingereicht: 22. Juli 2021
Angenommen: 15. Oktober 2021
Accepted Manuscript online:
23. November 2021
Artikel online veröffentlicht:
17. Januar 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/)
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Neuenschwander PF. COAGULATION CASCADE | Factor X. In: Laurent GJ, Shapiro SD. eds. Encyclopedia of Respiratory Medicine. Cambridge, Massachusetts: Academic Press; 2006: 499-503
- 2 Smith SA, Travers RJ, Morrissey JH. How it all starts: initiation of the clotting cascade. Crit Rev Biochem Mol Biol 2015; 50 (04) 326-336
- 3 Brown MA, Stenberg LM, Stenflo J. Coagulation Factor Xa. Handbook of Proteolytic Enzymes; 2013. 03. 2908-2915
- 4 Krishnaswamy S. The transition of prothrombin to thrombin. J Thromb Haemost 2013; 11 (Suppl. 01) 265-276
- 5 Mann KG, Jenny RJ, Krishnaswamy S. Cofactor proteins in the assembly and expression of blood clotting enzyme complexes. Annu Rev Biochem 1988; 57: 915-956
- 6 Schuepbach RA, Riewald M. Coagulation factor Xa cleaves protease-activated receptor-1 and mediates signaling dependent on binding to the endothelial protein C receptor. J Thromb Haemost 2010; 8 (02) 379-388
- 7 Soh UJ, Dores MR, Chen B, Trejo J. Signal transduction by protease-activated receptors. Br J Pharmacol 2010; 160 (02) 191-203
- 8 Girolami A, Cosi E, Sambado L, Girolami B, Randi ML. Complex history of the discovery and characterization of congenital factor X deficiency. Semin Thromb Hemost 2015; 41 (04) 359-365
- 9 Brown DL, Kouides PA. Diagnosis and treatment of inherited factor X deficiency. Haemophilia 2008; 14 (06) 1176-1182
- 10 Epcacan S, Menegatti M, Akbayram S, Cairo A, Peyvandi F, Oner AF. Frequency of the p.Gly262Asp mutation in congenital Factor X deficiency. Eur J Clin Invest 2015; 45 (10) 1087-1091
- 11 Karimi M, Yarmohammadi H, Ardeshiri R, Yarmohammadi H. Inherited coagulation disorders in southern Iran. Haemophilia 2002; 8 (06) 740-744
- 12 Al-Rahal NK. Inherited bleeding disorders in iraq and consanguineous marriage. Int J Hematol Oncol Stem Cell Res 2018; 12 (04) 273-281
- 13 Menegatti M, Peyvandi F. Factor X deficiency. Semin Thromb Hemost 2009; 35 (04) 407-415
- 14 Shapiro A. Plasma-derived human factor X concentrate for on-demand and perioperative treatment in factor X-deficient patients: pharmacology, pharmacokinetics, efficacy, and safety. Expert Opin Drug Metab Toxicol 2017; 13 (01) 97-104
- 15 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
- 16 Peyvandi F, Menegatti M. Treatment of rare factor deficiencies in 2016. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 663-669
- 17 Kram HB, Nathan RC, Stafford FJ, Fleming AW, Shoemaker WC. Fibrin glue achieves hemostasis in patients with coagulation disorders. Arch Surg 1989; 124 (03) 385-387
- 18 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80 (08) 1998-2005
- 19 Herrmann FH, Auerswald G, Ruiz-Saez A. et al; Greifswald Factor X Deficiency Study Group. Factor X deficiency: clinical manifestation of 102 subjects from Europe and Latin America with mutations in the factor 10 gene. Haemophilia 2006; 12 (05) 479-489
- 20 Saunders RE, O'Connell NM, Lee CA, Perry DJ, Perkins SJ. Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools. Hum Mutat 2005; 26 (03) 192-198
- 21 Saunders RE, Shiltagh N, Gomez K. et al. Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency. Thromb Haemost 2009; 102 (02) 287-301
- 22 Rallapalli PM, Kemball-Cook G, Tuddenham EG, Gomez K, Perkins SJ. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost 2013; 11 (07) 1329-1340
- 23 Harris VA, Lin W, Perkins SJ. Analysis of 272 genetic variants in the upgraded interactive FXI web database reveals new insights into FXI deficiency. 2021; (e-pub ahead of print) DOI: 10.1055/a-1683-8605.
- 24 Wang SX, Hur E, Sousa CA, Brinen L, Slivka EJ, Fletterick RJ. The extended interactions and GLA domain of blood coagulation factor Xa. Biochemistry 2003; 42 (26) 7959-7966
- 25 Kamata K, Kawamoto H, Honma T, Iwama T, Kim SH. Structural basis for chemical inhibition of human blood coagulation factor Xa. Proc Natl Acad Sci U S A 1998; 95 (12) 6630-6635
- 26 Williams CJ, Headd JJ, Moriarty NW. et al. MolProbity: more and better reference data for improved all-atom structure validation. Protein Sci 2018; 27 (01) 293-315
- 27 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
- 28 Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nat Protoc 2016; 11 (01) 1-9
- 29 Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the functional effect of amino acid substitutions and indels. PLoS One 2012; 7 (10) e46688
- 30 Grantham R. Amino acid difference formula to help explain protein evolution. Science 1974; 185 (4154): 862-864
- 31 Touw WG, Baakman C, Black J. et al. A series of PDB-related databanks for everyday needs. Nucleic Acids Res 2015; 43 (Database issue): D364-D368
- 32 Kabsch W, Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983; 22 (12) 2577-2637
- 33 Tien MZ, Meyer AG, Sydykova DK, Spielman SJ, Wilke CO. Maximum allowed solvent accessibilites of residues in proteins. PLoS One 2013; 8 (11) e80635
- 34 Karczewski KJ, Francioli LC, Tiao G. et al; Genome Aggregation Database Consortium. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581 (7809): 434-443
- 35 Messier TL, Wong CY, Bovill EG, Long GL, Church WR. Factor X Stockton: a mild bleeding diathesis associated with an active site mutation in factor X. Blood Coagul Fibrinolysis 1996; 7 (01) 5-14
- 36 Uprichard J, Perry DJ. Factor X deficiency. Blood Rev 2002; 16 (02) 97-110
- 37 Giansily-Blaizot M, Rallapalli PM, Perkins SJ. et al. The EAHAD blood coagulation factor VII variant database. Hum Mutat 2020; 41 (07) 1209-1219
- 38 Bock PE, Panizzi P, Verhamme IM. Exosites in the substrate specificity of blood coagulation reactions. J Thromb Haemost 2007; 5 (Suppl. 01) 81-94