Skip to main content
SpringerLink
Log in

A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome

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

Abstract

Background

Mutations in human ether-à-go-go-related gene (hERG) potassium channels are closely associated with long QT syndrome (LQTS). Previous studies have demonstrated that macrolide antibiotics increase the risk of cardiovascular diseases. To date, the mechanisms underlying acquired LQTS remain elusive.

Methods

A novel hERG mutation I1025N was identified in an azithromycin-treated patient with acquired long QT syndrome via Sanger sequencing. The mutant I1025N plasmid was transfected into HEK-293 cells, which were subsequently incubated with azithromycin. The effect of azithromycin and mutant I1025N on the hERG channel was evaluated via western blot, immunofluorescence, and electrophysiology techniques.

Results

The protein expression of the mature hERG protein was down-regulated, whereas that of the immature hERG protein was up-regulated in mutant I1025N HEK-293 cells. Azithromycin administration resulted in a negative effect on the maturation of the hERG protein. Additionally, the I1025N mutation exerted an inhibitory effect on hERG channel current. Moreover, azithromycin inhibited hERG channel current in a concentration-dependent manner. The I1025N mutation and azithromycin synergistically decreased hERG channel expression and hERG current. However, the I1025N mutation and azithromycin did not alter channel gating dynamics.

Conclusions

These findings suggest that hERG gene mutations might be involved in the genetic susceptibility mechanism underlying acquired LQTS induced by azithromycin.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

References

  1. Berthet M, Denjoy I, Donger C, Demay L, Hammoude H, Klug D, Schulze-Bahr E, Richard P, Funke H, Schwartz K et al (1999) C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. Circulation 99(11):1464–1470

    Article  CAS  PubMed  Google Scholar 

  2. Schwartz PJ, Crotti L, Insolia R (2012) Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol 5(4):868–877

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81(2):299–307

    Article  CAS  PubMed  Google Scholar 

  4. Warmke JW, Ganetzky B (1994) A family of potassium channel genes related to Eag in Drosophila and mammals. Proc Natl Acad Sci U S A 91(8):3438–3442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanguinetti MC, Tristani-Firouzi M (2006) hERG potassium channels and cardiac arrhythmia. Nature 440(7083):463–469

    Article  CAS  PubMed  Google Scholar 

  6. Perry MD, Ng CA, Mann SA, Sadrieh A, Imtiaz M, Hill AP, Vandenberg JI (2015) Getting to the heart of hERG K(+) channel gating. J Physiol 593(12):2575–2585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Volberg WA, Koci BJ, Su W, Lin J, Zhou J (2002) Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics. J Pharmacol Exp Ther 302(1):320–327

    Article  CAS  PubMed  Google Scholar 

  8. Wu Y, Bi WT, Qu LP, Fan J, Kong XJ, Ji CC, Chen XM, Yao FJ, Liu LJ, Cheng YJ et al (2023) Administration of macrolide antibiotics increases cardiovascular risk. Front Cardiovasc Med 10:1117254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Juurlink DN (2014) The cardiovascular safety of azithromycin. CMAJ 186(15):1127–1128

    Article  PubMed  PubMed Central  Google Scholar 

  10. Thomsen MB, Beekman JD, Attevelt NJ, Takahara A, Sugiyama A, Chiba K, Vos MA (2006) No proarrhythmic properties of the antibiotics Moxifloxacin or Azithromycin in anaesthetized dogs with chronic-AV block. Br J Pharmacol 149(8):1039–1048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cheng YJ, Nie XY, Chen XM, Lin XX, Tang K, Zeng WT, Mei WY, Liu LJ, Long M, Yao FJ et al (2015) The role of Macrolide antibiotics in increasing Cardiovascular Risk. J Am Coll Cardiol 66(20):2173–2184

    Article  CAS  PubMed  Google Scholar 

  12. Thomas D, Kiehn J, Katus HA, Karle CA (2003) Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res 60(2):235–241

    Article  CAS  PubMed  Google Scholar 

  13. Roden DM (2019) A current understanding of drug-induced QT prolongation and its implications for anticancer therapy. Cardiovasc Res 115(5):895–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Crumb W, Cavero II (1999) QT interval prolongation by non-cardiovascular drugs: issues and solutions for novel drug development. Pharm Sci Technol Today 2(7):270–280

    Article  CAS  PubMed  Google Scholar 

  15. Giudicessi JR, Ackerman MJ (2013) Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused? Cleve Clin J Med 80(9):539–544

    Article  PubMed  PubMed Central  Google Scholar 

  16. Salem JE, Dureau P, Bachelot A, Germain M, Voiriot P, Lebourgeois B, Tregouet DA, Hulot JS, Funck-Brentano C (2018) Association of oral contraceptives with Drug-Induced QT interval prolongation in healthy Nonmenopausal women. JAMA Cardiol 3(9):877–882

    Article  PubMed  PubMed Central  Google Scholar 

  17. Gagliano-Juca T, Icli TB, Pencina KM, Li Z, Tapper J, Huang G, Travison TG, Tsitouras P, Harman SM, Storer TW et al (2017) Effects of Testosterone replacement on Electrocardiographic Parameters in men: findings from two randomized trials. J Clin Endocrinol Metab 102(5):1478–1485

    Article  PubMed  Google Scholar 

  18. Dunker A, Kolanczyk DM, Maendel CM, Patel AR, Pettit NN (2016) Impact of the FDA Warning for Azithromycin and risk for QT prolongation on utilization at an Academic Medical Center. Hosp Pharm 51(10):830–833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Behr ER, Roden D (2013) Drug-induced arrhythmia: pharmacogenomic prescribing? Eur Heart J 34(2):89–95

    Article  PubMed  Google Scholar 

  20. Itoh H, Sakaguchi T, Ding WG, Watanabe E, Watanabe I, Nishio Y, Makiyama T, Ohno S, Akao M, Higashi Y et al (2009) Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. Circ Arrhythm Electrophysiol 2(5):511–523

    Article  CAS  PubMed  Google Scholar 

  21. Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH, Shimizu W, Schwartz PJ, Stanton M et al (2002) Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation 105(16):1943–1948

    Article  CAS  PubMed  Google Scholar 

  22. El-Sherif N, Turitto G, Boutjdir M (2019) Acquired long QT syndrome and Electrophysiology of Torsade De Pointes. Arrhythm Electrophysiol Rev 8(2):122–130

    Article  PubMed  PubMed Central  Google Scholar 

  23. Vandenberg JI, Perry MD, Perrin MJ, Mann SA, Ke Y, Hill AP (2012) hERG K(+) channels: structure, function, and clinical significance. Physiol Rev 92(3):1393–1478

    Article  CAS  PubMed  Google Scholar 

  24. Takemasa H, Nagatomo T, Abe H, Kawakami K, Igarashi T, Tsurugi T, Kabashima N, Tamura M, Okazaki M, Delisle BP et al (2008) Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome. Br J Pharmacol 153(3):439–447

    Article  CAS  PubMed  Google Scholar 

  25. Whicher JR, MacKinnon R (2016) Structure of the voltage-gated K(+) channel Eag1 reveals an alternative voltage sensing mechanism. Science 353(6300):664–669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mikosch M, Homann U (2009) How do ER export motifs work on ion channel trafficking? Curr Opin Plant Biol 12(6):685–689

    Article  CAS  PubMed  Google Scholar 

  27. Vonderlin N, Fischer F, Zitron E, Seyler C, Scherer D, Thomas D, Katus HA, Scholz EP (2015) Anesthetic drug midazolam inhibits cardiac human ether-a-go-go-related gene channels: mode of action. Drug Des Devel Ther 9:867–877

    PubMed  PubMed Central  Google Scholar 

  28. Berecki G, Zegers JG, Verkerk AO, Bhuiyan ZA, de Jonge B, Veldkamp MW, Wilders R, van Ginneken AC (2005) HERG channel (dys)function revealed by dynamic action potential clamp technique. Biophys J 88(1):566–578

    Article  CAS  PubMed  Google Scholar 

  29. Bohnen MS, Peng G, Robey SH, Terrenoire C, Iyer V, Sampson KJ, Kass RS (2017) Molecular pathophysiology of congenital long QT syndrome. Physiol Rev 97(1):89–134

    Article  CAS  PubMed  Google Scholar 

  30. Anderson CL, Kuzmicki CE, Childs RR, Hintz CJ, Delisle BP, January CT (2014) Large-scale mutational analysis of Kv11.1 reveals molecular insights into type 2 long QT syndrome. Nat Commun 5:5535

    Article  CAS  PubMed  Google Scholar 

  31. Akhavan A, Atanasiu R, Noguchi T, Han W, Holder N, Shrier A (2005) Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization. J Cell Sci 118(Pt 13):2803–2812

    Article  CAS  PubMed  Google Scholar 

  32. Camacho J (2006) Ether a go-go potassium channels and cancer. Cancer Lett 233(1):1–9

    Article  CAS  PubMed  Google Scholar 

  33. Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, Postema P, Beekman L, Walsh R, Hasegawa K, Barc J, Ernsting M et al (2020) Transethnic Genome-Wide Association Study provides insights in the Genetic Architecture and Heritability of Long QT Syndrome. Circulation 142(4):324–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sordillo PP, Sordillo DC, Helson L (2015) Review: the prolonged QT interval: role of pro-inflammatory cytokines, reactive oxygen species and the Ceramide and Sphingosine-1 phosphate pathways. In Vivo 29(6):619–636

    CAS  Google Scholar 

  35. Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T et al (2016) The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J 37(18):1456–1464

    Article  PubMed  Google Scholar 

  36. Szendrey M, Guo J, Li W, Yang T, Zhang S (2021) COVID-19 drugs Chloroquine and Hydroxychloroquine, but not azithromycin and remdesivir, Block hERG Potassium channels. J Pharmacol Exp Ther 377(2):265–272

    Article  CAS  PubMed  Google Scholar 

  37. Lee W, Windley MJ, Perry MD, Vandenberg JI, Hill AP (2019) Protocol-dependent differences in IC(50) values measured in human ether-a-go-go-related gene assays occur in a predictable way and can be used to quantify state preference of drug binding. Mol Pharmacol 95(5):537–550

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

The study was also financially supported by grants from the National Natural Science Foundation of China (81600260, 82270333), Guangdong Basic and Applied Basic Research Foundation (2021A1515010405, 2022A1515012358), and High-level Talents Introduction Plan of Guangdong Provincial People’s Hospital (KY012023007).

Author information

Author notes

  1. Yun-Jiu Cheng, Yang Wu and Hui-Qiang Wei contributed equally to this work.

Authors and Affiliations

  1. Department of Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Yun-Jiu Cheng & Hui-Qiang Wei

  2. Department of Cardiovascular Medicine, People’s Hospital of Macheng City, Macheng, China

    Wen-Tao Bi

  3. The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China

    Yun-Jiu Cheng

  4. Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

    Yang Wu, Li-Ping Qu, Yue-Han Pan & Li-Juan Liu

  5. NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China

    Yang Wu, Li-Ping Qu, Yue-Han Pan & Li-Juan Liu

  6. The First Clinical Medical College, Guangdong Medical University, Zhanjiang, China

    Yi-Jian Liao

Authors
  1. Yun-Jiu Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui-Qiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi-Jian Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Ping Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yue-Han Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li-Juan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen-Tao Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YJC, YW and WTB figured and planned the experiments. YW, HQW, YJL, LPQ, YHP, and LJL implemented the experiments. HQW, YJL, LPQ and YJC analyzed the data. YJC and WTB wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Li-Juan Liu or Wen-Tao Bi.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of Guangdong Provincial People’s Hospital (NO.KY2023-182-02), and the participant provided written informed consent.

Competing interests

No potential conflicts of interest were revealed by any of the authors after they completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Additional information

Publisher’s Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, YJ., Wu, Y., Wei, HQ. et al. A novel mutation in hERG gene associated with azithromycin-induced acquired long QT syndrome. Mol Biol Rep 51, 520 (2024). https://doi.org/10.1007/s11033-024-09421-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11033-024-09421-9

Keywords

Search

Navigation