Skip to main content

Advertisement

SpringerLink
Log in

Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine-resistant familial Mediterranean fever patients

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Familial Mediterranean fever is a hereditary autoinflammatory syndrome. The typical treatment for the disease is colchicine. However, a subset of patients are not responsive to colchicine. In this study, polymorphisms in the colchicine-binding site of the TUBB1 gene, which encodes a tubulin isoform specific to leukocytes, were investigated in patients with colchicine-resistant disease. FMF patients who were followed in the Department of Pediatric Rheumatology at Hacettepe University were included in this study. Colchicine resistance was defined as ongoing disease activity (≥ 1 attack/month over 3 months or persistently elevated CRP) while taking the maximum tolerated dose of colchicine. A total of 62 Turkish FMF patients (42 colchicine-responsive and 20 colchicine-resistant) and a control group of healthy children were included in the study. DNA was extracted for analysis of TUBB1, and the colchicine binding site was sequenced. We did not observe A248T (rs148237574) or M257V (rs759579888), two variations that were previously associated with colchicine resistance in an in silico analysis. We did detect T274M (rs35565630), R306H (rs772479017), and R307H (rs6070697) variants in the FMF patients, but there was no statistically significant difference between the colchicine-responsive and colchicine-resistant groups. This is the first study to evaluate TUBB1 gene polymorphisms in the colchicine binding site in patients with FMF. Our data do not support the hypothesis that these polymorphisms are a possible cause of colchicine resistance in FMF patients.

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. Orphanet: Familial Mediterranean Fever. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=342. Accessed 6 Feb 2020

  2. Ece A, Çakmak E, Uluca Ü, Kelekci S, Yolbas I, Gunes A et al (2014) The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. Rheumatol Int 34:207–212. https://doi.org/10.1007/s00296-013-2858-1

    Article  CAS  PubMed  Google Scholar 

  3. Infevers - Tabular list. https://infevers.umai-montpellier.fr/web/search.php?n=1. Accessed 6 Feb 2020

  4. Akbaba TH (2019) Investigation of inflammasome components during cell migration process in autoinflammatory diseases. Thesis, Hacettepe University

  5. Goldfinger SE (1972) Colchicine for familial Mediterranean fever. N Engl J Med 287:1302

    CAS  PubMed  Google Scholar 

  6. Slobodnick A, Shah B, Krasnokutsky S, Pillinger MH (2017) Update on colchicine. Rheumatology 57:i4–i11. https://doi.org/10.1093/rheumatology/kex453

    Article  CAS  Google Scholar 

  7. Park YH, Wood G, Kastner DL, Chae JJ (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 17:914–921. https://doi.org/10.1038/ni.3457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Krendel M, Zenke FT, Bokoch GM (2002) Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat Cell Biol 4:294–301. https://doi.org/10.1038/ncb773

    Article  CAS  PubMed  Google Scholar 

  9. Livneh A, Zemer D, Langevitz P, Shemer J, Sohar E, Pras M (1993) Colchicine in the treatment of AA and AL amyloidosis. Semin Arthritis Rheum 23:206–214. https://doi.org/10.1016/s0049-0172(05)80042-3

    Article  CAS  PubMed  Google Scholar 

  10. Ozen S, Kone-Paut I, Gül A (2017) Colchicine resistance and intolerance in familial Mediterranean fever: definition, causes, and alternative treatments. Semin Arthritis Rheum 47:115–120

    Article  CAS  Google Scholar 

  11. Lidar M, Yonath H, Shechter N, Sikron F, Sadetzki S, Langevitz P et al (2012) Incomplete response to colchicine in M694V homozygote FMF patients. Autoimmun Rev 12:72–76

    Article  CAS  Google Scholar 

  12. Ozen F, Silan C, Uludag A, Candan F, Silan F, Ozdemir S et al (2011) Association between ABCB1 (MDR1) gene 3435 C > T polymorphism and colchicine unresponsiveness of FMF Patients. Ren Fail 33:899–903. https://doi.org/10.3109/0886022X.2011.605980

    Article  CAS  PubMed  Google Scholar 

  13. Sahakyan H, Abelyan N, Arakelov V, Arakelov G, Nazaryan K (2019) In silico study of colchicine resistance molecular mechanisms caused by tubulin structural polymorphism. PLoS ONE. https://doi.org/10.1371/journal.pone.0221532

    Article  PubMed  PubMed Central  Google Scholar 

  14. Prota AE, Danel F, Bachmann F, Bargsten K, Buey RM, Pohlmann J et al (2014) The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization. J Mol Biol 426:1848–1860. https://doi.org/10.1016/j.jmb.2014.02.005

    Article  CAS  PubMed  Google Scholar 

  15. Lu Y, Chen J, Xiao M, Li W, Miller DD (2012) An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm Res 29:2943–2971

    Article  CAS  Google Scholar 

  16. Ravelli RBG, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A et al (2004) Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature 428:198–202. https://doi.org/10.1038/nature02393

    Article  CAS  PubMed  Google Scholar 

  17. Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I et al (2019) Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78:1025–1032. https://doi.org/10.1136/annrheumdis-2019-215048

    Article  CAS  PubMed  Google Scholar 

  18. Yalçinkaya F, Ozen S, Ozçakar ZB, Aktay N, Cakar N, Düzova A et al (2009) A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology 48:395–398. https://doi.org/10.1093/rheumatology/ken509

    Article  PubMed  Google Scholar 

  19. Demirkaya E, Acikel C, Hashkes P, Gattorno M, Gul A, Ozdogan H et al (2016) Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis 75(6):1051–1056. https://doi.org/10.1136/annrheumdis-2015-208671

    Article  PubMed  Google Scholar 

  20. Leandro-García LJ, Leskelä S, Inglada-Pérez L, Landa I, de Cubas AA, Maliszewska A et al (2012) Hematologic β-tubulin VI isoform exhibits genetic variability that influences paclitaxel toxicity. Cancer Res 72:4744–4752. https://doi.org/10.1158/0008-5472.CAN-11-2861

    Article  CAS  PubMed  Google Scholar 

  21. Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R et al (2016) Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep 15:857–865. https://doi.org/10.1016/j.celrep.2016.03.075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Basciano PA, Matakas J, Pecci A, Civaschi E, Cagioni C, Bompiani N et al (2015) β-1 Tubulin R307H SNP alters microtubule dynamics and affects severity of a hereditary thrombocytopenia. J Thromb Haemost 13:651–659. https://doi.org/10.1111/jth.12824

    Article  CAS  PubMed  Google Scholar 

  23. Balci-Peynircioglu B, Akkaya-Ulum YZ, Akbaba TH, Tavukcuoglu Z (2019) Potential of miRNAs to predict and treat inflammation from the perspective of familial Mediterranean fever. Inflamm Res 68:905–913

    Article  CAS  Google Scholar 

  24. Akbaba TH, Balcı-Peynircioğlu B (2018) Potential impacts of gut microbiota on immune system related diseases: current studies and future challenges. Acta Med 49:31–37

    Google Scholar 

Download references

Acknowledgements

Advanced English Language editing service was supplied by Hacettepe Teknokent Technology Transfer Center (HT-TTM).

Funding

This study was supported by the Scientific and Technological Research Council of Turkey (TÜBİTAK, Project Number: 218S522).

Author information

Authors and Affiliations

  1. Department of Medical Biology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Tayfun Hilmi Akbaba, Gizem Ustabas & Banu Balci-Peynircioglu

  2. Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Muserref Kasap-Cuceloglu & Seza Ozen

Authors
  1. Tayfun Hilmi Akbaba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gizem Ustabas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muserref Kasap-Cuceloglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seza Ozen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Banu Balci-Peynircioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

THA and BBP designed and drafted the work; MK and SO determined the study groups and analyzed the clinical information; THA and GU performed the experiments; THA and MC wrote the manuscript; and BBP and SO finalized the manuscript for submission. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Banu Balci-Peynircioglu.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Consent for publication

All authors agree on publishing.

Ethics approval

The study was approved by the Non-interventional Clinical Research Ethics Board of Hacettepe University (2020/01-40). Written informed consent was obtained from all patients and their parents.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

11033_2020_5957_MOESM1_ESM.tif

Supplementary material 1 (TIF 69 kb) Figure S1: Agarose gel image of the PCR products of a fragment encoding the colchicine-binding site of TUBB1 in FMF patients and control individuals. (S: severe FMF patients, M: mild FMF patients, C: control, NTC: no template control)

11033_2020_5957_MOESM2_ESM.docx

Supplementary material 2 (DOCX 13 kb) Table S1. Chi-square analysis (χ2) of the R307H polymorphism between the FMF patient and control groups.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akbaba, T.H., Ustabas, G., Kasap-Cuceloglu, M. et al. Analysis of polymorphisms in the colchicine binding site of tubulin in colchicine-resistant familial Mediterranean fever patients. Mol Biol Rep 47, 9005–9011 (2020). https://doi.org/10.1007/s11033-020-05957-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05957-8

Keywords

Search

Navigation