Skip to main content
SpringerLink
Log in

Mutation Analysis of F11 Gene in Patients with FXI Deficiency in Russia

  • HUMAN GENETICS
  • Published:
Russian Journal of Genetics Aims and scope Submit manuscript

Abstract

Factor FXI is an essential participant of the blood coagulation cascade and is coded by the F11 gene, mutations in which lead to an extremely rare (1 : 1 000 000) autosomal disease—FXI deficiency, also known as hemophilia C. The most frequently, FXI deficiency is diagnosed in Ashkenazi Jews with three major mutations. The aim of this study was a primary description of the F11 gene mutational spectrum in the Russian population. During the study, we sequenced all functionally important regions of the F11 gene for 11 unrelated patients with hemophilia C. In total, ten different gene defects were revealed: five missense mutations, one nonsense mutation, three frameshift deletions, and one inframe deletion. All of them were uniformly distributed across the gene. Among the most frequent genetic defects in the world population, we found only type II mutation p.Glu135Ter common in Ashkenazi Jews in our sample. Two previously undescribed variants (c.1768del and p.His53Tyr) were evaluated as probably pathogenic. There was a typical picture of incomplete dominance by laboratory parameters—a significant decline of FXI activity level and an increase in APTT when both copies of the gene were damaged and slight deviations from the norm if only one of the copies was impaired. To sum up, we described F11 defects in Russian patients with FXI deficiency. Our findings indicate a high level of heterogeneity of the mutational spectrum leading to hemophilia C in Russia.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.

Similar content being viewed by others

REFERENCES

  1. Emsley, J., McEwan, P.A., and Gailani, D., Structure and function of factor XI, Blood, 2010, vol. 115, no. 13, pp. 2569—2577. https://doi.org/10.1182/blood-2009-09-199182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Calderara, D.B., Zermatten, M.G., Aliotta, A., and Alberio, L., How to capture the bleeding phenotype in FXI-deficient patients, Hamostaseologie, 2020, vol. 40, no. 4, pp. 491—499. https://doi.org/10.1055/a-1227-8122

    Article  Google Scholar 

  3. Harris, V.A., Lin, W., and Perkins, S.J., Analysis of 272 genetic variants in the upgraded interactive FXI web database reveals new insights on FXI deficiency, TH Open, 2021, vol. 5, no. 4, pp. e543—e556. https://doi.org/10.1055/a-1683-8605

    Article  PubMed  PubMed Central  Google Scholar 

  4. Seligsohn, U., Factor XI deficiency in humans, J. Thromb. Haemost., 2009, vol. 7, suppl. 1, pp. 84—87. https://doi.org/10.1111/j.1538-7836.2009.03395

    Article  CAS  PubMed  Google Scholar 

  5. Asselta, R., Paraboschi, E.M., Rimoldi, V., et al., Exploring the global landscape of genetic variation in coagulation factor XI deficiency, Blood, 2017, vol. 130, no. 4, pp. e1—e6. https://doi.org/10.1182/blood-2017-04-780148

    Article  CAS  PubMed  Google Scholar 

  6. Asakai, R., Chung, D.W., Ratnoff, O.D., and Davie, E.W., 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, vol. 86, no. 20, pp. 7667—7671. https://doi.org/10.1073/pnas.86.20.7667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Peretz, H., Mulai, A., Usher, S., et al., The two common mutations causing factor XI deficiency in Jews stem from distinct founders: one of ancient Middle Eastern origin and another of more recent European origin, Blood, 1997, vol. 90, no. 7, pp. 2654—2659.

    Article  CAS  Google Scholar 

  8. Peretz, H., Salomon, O., Mor-Cohen, R., et al., Type I mutation in the F11 gene is a third ancestral mutation which causes factor XI deficiency in Ashkenazi Jews, J. Thromb. Haemost., 2013, vol. 11, no. 4, pp. 724—730. https://doi.org/10.1111/jth.12137

    Article  CAS  PubMed  Google Scholar 

  9. 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, vol. 85, no. 2, pp. 429—432.

    Article  CAS  Google Scholar 

  10. Kim, J., Song, J., Lyu, C.J., et al., Population-specific spectrum of the F11 mutations in Koreans: evidence for a founder effect, Clin. Genet., 2012, vol. 82, no. 2, pp. 180—186. https://doi.org/10.1111/j.1399-0004.2011.01732.x

    Article  CAS  PubMed  Google Scholar 

  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, vol. 27, no. 8, p. 829. https://doi.org/10.1002/humu.9439

    Article  PubMed  Google Scholar 

  12. Zucker, M., Zivelin, A., Landau, M., et al., Characterization of seven novel mutations causing factor XI deficiency, Haematologica, 2007, vol. 92, no. 10, pp. 1375—1380. https://doi.org/10.3324/haematol.11526

    Article  CAS  PubMed  Google Scholar 

  13. Gueguen, P., Chauvin, A., Quemener-Redon, S., et al., Revisiting the molecular epidemiology of factor XI deficiency: nine new mutations and an original large 4qTer deletion in western Brittany (France), Thromb. Haemost., 2012, vol. 107, no. 1, pp. 44—50. https://doi.org/10.1160/TH11-06-0415

    Article  CAS  PubMed  Google Scholar 

  14. Liu, H., Wang, H.F., Tang, L., et al., Genetic analysis in Factor XI deficient patients from central China: identification of one novel and seven recurrent mutations, Gene, 2015, vol. 561, no. 1, pp. 101—106. https://doi.org/10.1016/j.gene.2015.02.021

    Article  CAS  PubMed  Google Scholar 

  15. Shao, Y., Cao, Y., Lu, Y., et al., Clinical manifestations and mutation spectrum of 57 subjects with congenital factor XI deficiency in China, Blood Cells, Mol. Dis., 2016, vol. 58, pp. 29—34. https://doi.org/10.1016/j.bcmd.2016.01.004

    Article  CAS  Google Scholar 

  16. Esteban, J., de la Morena-Barrio, M.E., Salloum-Asfar, S., et al., High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: results from the Yecla study, Haemophilia, 2017, vol. 23, no. 6, pp. e488—e496. https://doi.org/10.1111/hae.13356

    Article  CAS  PubMed  Google Scholar 

  17. Colakoglu, S., Bayhan, T., Tavil, B., et al., Molecular genetic analysis of the F11 gene in 14 Turkish patients with factor XI deficiency: identification of novel and recurrent mutations and their inheritance within families, Blood Transfus., 2018, vol. 16, no. 1, pp. 105—113. https://doi.org/10.2450/2016.0098-16

    Article  PubMed  PubMed Central  Google Scholar 

  18. Schwarz, J.M., Cooper, D.N., Schuelke, M., and Seelow, D., MutationTaster2: mutation prediction for the deep-sequencing age, Nat. Methods, 2014, vol. 11, no. 4, pp. 361—362. https://doi.org/10.1038/nmeth.2890

    Article  CAS  PubMed  Google Scholar 

  19. Adzhubei, I.A., Schmidt, S., Peshkin, L., et al., A method and server for predicting damaging missense mutations, Nat. Methods, 2010, vol. 7, no. 4, pp. 248—249. https://doi.org/10.1038/nmeth0410-248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Choi, Y., Sims, G.E., Murphy, S., et al., Predicting the functional effect of amino acid substitutions and indels, PLoS One, 2012, vol. 7, no. 10. e46688. https://doi.org/10.1371/journal.pone.0046688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sim, N.L., Kumar, P., Hu, J., et al., SIFT web server: predicting effects of amino acid substitutions on proteins, Nuclec Acids Res., 2012, vol. 40, pp. W452—W457. https://doi.org/10.1093/nar/gks539

    Article  CAS  Google Scholar 

  22. Shihab, H.A., Gough, J., Cooper, D.N., et al., Predicting the functional consequences of cancer-associated amino acid substitutions, Bioinformatics, 2013, vol. 29, no. 12, pp. 1504—1510. https://doi.org/10.1093/bioinformatics/btt182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zadra, G., Asselta, R., Malcovati, M., et al., Molecular genetic analysis of severe coagulation factor XI deficiency in six Italian patients, Haematologica, 2004, vol. 89, no. 11, pp. 1332—1340.

    CAS  PubMed  Google Scholar 

  24. Dai, L., Rangarajan, S., and Mitchell, M., Three dominant-negative mutations in factor XI-deficient patients, Haemophilia, 2011, vol. 17, no. 5, pp. e919—e922. https://doi.org/10.1111/j.1365-2516.2011.02519.x

    Article  CAS  PubMed  Google Scholar 

  25. Mulder, R., Wiewel-Verschueren, S., Meijer, K., and Mulder, A.B., Identification of a novel factor XI gene mutational event in a Dutch Caucasian family with inherited factor XI deficiency, Thromb. Haemost., 2013, vol. 109, no. 6, pp. 1183—1185. https://doi.org/10.1160/TH12-12-0933

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Research Center for Hematology, 125167, Moscow, Russia

    O. S. Pshenichnikova, V. L. Surin, N. V. Sats, E. V. Yakovleva, O. S. Dimitrieva & N. I. Zozulya

Authors
  1. O. S. Pshenichnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. L. Surin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. V. Sats
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. V. Yakovleva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O. S. Dimitrieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. I. Zozulya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. S. Pshenichnikova.

Ethics declarations

Conflict of interest. The authors declare that they have no conflicts of interest.

Statement of compliance with standards of research involving humans as subjects. All procedures performed in a study involving people comply with the ethical standards of the institutional and/or national committee for research ethics and the 1964 Helsinki Declaration and its subsequent changes or comparable ethical standards.

Informed voluntary consent was obtained from each of the participants.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pshenichnikova, O.S., Surin, V.L., Sats, N.V. et al. Mutation Analysis of F11 Gene in Patients with FXI Deficiency in Russia. Russ J Genet 58, 829–834 (2022). https://doi.org/10.1134/S1022795422070134

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S1022795422070134

Keywords:

Search

Navigation