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

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.

Keywords

coagulation factors - haemostasis - protein structure/folding - inherited coagulation disorders - gene mutations

Research Grants and Financial Support

The authors were supported by grants from the Lister Institute for Preventive Medicine for this work.

Publication History

Received: 04 May 2021

Accepted: 27 October 2021

Accepted Manuscript online:
01 November 2021

Article published online:
17 January 2022

• References

• 1 Mohammed BM, Matafonov A, Ivanov I. et al. An update on factor XI structure and function. Thromb Res 2018; 161: 94-105
• 2 Berber E. Molecular characterization of FXI deficiency. Clin Appl Thromb Hemost 2011; 17 (01) 27-32
• 3 Tordai H, Bányai L, Patthy L. The PAN module: the N-terminal domains of plasminogen and hepatocyte growth factor are homologous with the apple domains of the prekallikrein family and with a novel domain found in numerous nematode proteins. FEBS Lett 1999; 461 (1-2): 63-67
• 4 Gailani D, Smith SB. Structural and functional features of factor XI. J Thromb Haemost 2009; 7 (Suppl. 01) 75-78
• 5 Ponczek MB, Shamanaev A, LaPlace A. et al. The evolution of factor XI and the kallikrein-kinin system. Blood Adv 2020; 4 (24) 6135-6147
• 6 Geng Y, Verhamme IM, Smith SB. et al. The dimeric structure of factor XI and zymogen activation. Blood 2013; 121 (19) 3962-3969
• 7 Bar Barroeta A, van Galen J, Stroo I, Marquart JA, Meijer AB, Meijers JCM. Hydrogen-deuterium exchange mass spectrometry highlights conformational changes induced by factor XI activation and binding of factor IX to factor XIa. J Thromb Haemost 2019; 17 (12) 2047-2055
• 8 Rosenthal RL, Dreskin OH, Rosenthal N. New hemophilia-like disease caused by deficiency of a third plasma thromboplastin factor. Proc Soc Exp Biol Med 1953; 82 (01) 171-174
• 9 Wheeler AP, Gailani D. Why factor XI deficiency is a clinical concern. Expert Rev Hematol 2016; 9 (07) 629-637
• 10 Martín-Salces M, Jimenez-Yuste V, Alvarez MT, Quintana M, Hernández-Navarro F. Review: Factor XI deficiency: review and management in pregnant women. Clin Appl Thromb Hemost 2010; 16 (02) 209-213
• 11 Mitchell M, Mountford R, Butler R. et al. Spectrum of factor XI (F11) mutations in the UK population–116 index cases and 140 mutations. Hum Mutat 2006; 27 (08) 829
• 12 Shpilberg O, Peretz H, Zivelin A. et al. One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews. Blood 1995; 85 (02) 429-432
• 13 Asselta R, Paraboschi EM, Rimoldi V. et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood 2017; 130 (04) e1-e6
• 14 Asakai R, Chung DW, Ratnoff OD, Davie EW. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci U S A 1989; 86 (20) 7667-7671
• 15 Quélin F, Trossaërt M, Sigaud M, Mazancourt PD, Fressinaud E. Molecular basis of severe factor XI deficiency in seven families from the west of France. Seven novel mutations, including an ancient Q88X mutation. J Thromb Haemost 2004; 2 (01) 71-76
• 16 Zivelin A, Bauduer F, Ducout L. et al. Factor XI deficiency in French Basques is caused predominantly by an ancestral Cys38Arg mutation in the factor XI gene. Blood 2002; 99 (07) 2448-2454
• 17 Bolton-Maggs PH, Peretz H, Butler R. et al. A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost 2004; 2 (06) 918-924
• 18 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
• 19 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
• 20 Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat 2011; 32 (05) 557-563
• 21 Gasteiger E, Gattiker A, Hoogland C, Ivanyi I, Appel RD, Bairoch A. ExPASy: The proteomics server for in-depth protein knowledge and analysis. Nucleic Acids Res 2003; 31 (13) 3784-3788
• 22 Landrum MJ, Lee JM, Benson M. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 2016; 44 (D1): D862-D868
• 23 Stenson PD, Ball EV, Mort M, Phillips AD, Shaw K, Cooper DN. The Human Gene Mutation Database (HGMD) and its exploitation in the fields of personalized genomics and molecular evolution. Curr Protoc Bioinformatics. 2012; Chapter 1:Unit 1.13.
• 24 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
• 25 Li C, Voos KM, Pathak M. et al. Plasma kallikrein structure reveals apple domain disc rotated conformation compared to factor XI. J Thromb Haemost 2019; 17 (05) 759-770
• 26 Papagrigoriou E, McEwan PA, Walsh PN, Emsley J. Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 2006; 13 (06) 557-558
• 27 Krissinel E, Henrick K. Inference of macromolecular assemblies from crystalline state. J Mol Biol 2007; 372 (03) 774-797
• 28 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
• 29 Kabsch W, Sander C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 1983; 22 (12) 2577-2637
• 30 Tien MZ, Meyer AG, Sydykova DK, Spielman SJ, Wilke CO. Maximum allowed solvent accessibilites of residues in proteins. PLoS One 2013; 8 (11) e80635
• 31 Emsley J, McEwan PA, Gailani D. Structure and function of factor XI. Blood 2010; 115 (13) 2569-2577
• 32 Orengo CA, Taylor WR. SSAP: sequential structure alignment program for protein structure comparison. Methods Enzymol 1996; 266: 617-635
• 33 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
• 34 Vaser R, Adusumalli S, Leng SN, Sikic M, Ng PC. SIFT missense predictions for genomes. Nat Protoc 2016; 11 (01) 1-9
• 35 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
• 36 Grantham R. Amino acid difference formula to help explain protein evolution. Science 1974; 185 (4154): 862-864
• 37 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
• 38 Laskowski RA, Jabłońska J, Pravda L, Vařeková RS, Thornton JM. PDBsum: Structural summaries of PDB entries. Protein Sci 2018; 27 (01) 129-134
• 39 McMullen BA, Fujikawa K, Davie EW. Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains. Biochemistry 1991; 30 (08) 2056-2060
• 40 Meijers JC, Mulvihill ER, Davie EW, Chung DW. Apple four in human blood coagulation factor XI mediates dimer formation. Biochemistry 1992; 31 (19) 4680-4684
• 41 Osborne AJ, Breno M, Borsa NG. et al. Statistical validation of rare complement variants provides insights into the molecular basis of atypical hemolytic uremic syndrome and C3 glomerulopathy. J Immunol 2018; 200 (07) 2464-2478
• 42 Giansily-Blaizot M, Rallapalli PM, Perkins SJ. et al. The EAHAD blood coagulation factor VII variant database. Hum Mutat 2020; 41 (07) 1209-1219
• 43 Saunders RE, Abarrategui-Garrido C, Frémeaux-Bacchi V. et al. The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models. Hum Mutat 2007; 28 (03) 222-234
• 44 Perkins SJ. Genetic and protein structural evaluation of atypical hemolytic uremic syndrome and C3 glomerulopathy. Adv Chronic Kidney Dis 2020; 27 (02) 120-127.e4