SpringerLink
Log in

Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening

  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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.

Data Availability

The original contribution presented in the study is publicly available in the ClinVar repository (https://www.ncbi.nlm.nih.gov/clinvar/) using accession number VCV000405343.40.

Abbreviations

AP:

action potential

BrS:

Brugada syndrome

CHO-K1:

Chinese hamster ovary cells

VUS:

variant of uncertain significance

References

  1. Cerrone, M., Costa, S., and Delmar, M. (2022) The genetics of Brugada syndrome, Annu. Rev. Genom. Hum. Genet., 23, 255-274, https://doi.org/10.1146/annurev-genom-112921-011200.

    Article  CAS  Google Scholar 

  2. Chen, Q., Kirsch, G. E., Zhang, D., Brugada, R., Brugada, J., Brugada, P., Potenza, D., Moya, A., Borggrefe, M., Breithardt, G., Ortiz-Lopez, R., Wang, Z., Antzelevitch, C., O’Brien, R. E., Schulze-Bahr, E., Keating, M. T., Towbin, J. A., and Wang, Q. (1998) Genetic basis and molecular mechanism for idiopathic ventricular fibrillation, Nature, 392, 293-296, https://doi.org/10.1038/32675.

    Article  CAS  PubMed  Google Scholar 

  3. Brugada, J., Campuzano, O., Arbelo, E., Sarquella-Brugada, G., and Brugada, R. (2018) Present status of Brugada syndrome: JACC state-of-the-art review, J. Am. Coll. Cardiol., 72, 1046-1059, https://doi.org/10.1016/j.jacc.2018.06.037.

    Article  PubMed  Google Scholar 

  4. Priori, S. G., Napolitano, C., Schwartz, P. J., Bloise, R., Crotti, L., and Ronchetti, E. (2000) The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge, Circulation, 102, 945-947, https://doi.org/10.1161/01.CIR.102.9.945.

    Article  CAS  PubMed  Google Scholar 

  5. Wilde, A. A. M., Semsarian, C., Márquez, M. F., Shamloo, A. S., Ackerman, M. J., Ashley, E. A., Sternick, E. B., Barajas-Martinez, H., Behr, E. R., Bezzina, C. R., Breckpot, J., Charron, P., Chockalingam, P., Crotti, L., Gollob, M. H., Lubitz, S., Makita, N., Ohno, S., Ortiz-Genga, M., Sacilotto, L., Schulze-Bahr, E., Shimizu, W., Sotoodehnia, N., Tadros, R., Ware, J. S., Winlaw, D. S., Kaufman, E. S., et al. (2022) European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases, Europace, 24, 1307-1367, https://doi.org/10.1093/europace/euac030.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Zhang, J., Sacher, F., Hoffmayer, K., O’Hara, T., Strom, M., Cuculich, P., Silva, J., Cooper, D., Faddis, M., Hocini, M., Haïssaguerre, M., Scheinman, M., and Rudy, Y. (2015) Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients, Circulation, 131, 1950-1959, https://doi.org/10.1161/CIRCULATIONAHA.114.013698.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Campuzano, O., Fernandez-Falgueras, A., Lemus, X., Sarquella-Brugada, G., Cesar, S., Coll, M., Mates, J., Arbelo, E., Jordà, P., Perez-Serra, A., Del Olmo, B., Ferrer-Costa, C., Iglesias, A., Fiol, V., Puigmulé, M., Lopez, L., Pico, F., Brugada, J., and Brugada, R. (2019) Short QT syndrome: a comprehensive genetic interpretation and clinical translation of rare variants, J. Clin. Med., 8, 1035, https://doi.org/10.3390/jcm8071035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Béziau, D. M., Barc, J., O’Hara, T., Le Gloan, L., Amarouch, M. Y., Solnon, A., Pavin, D., Lecointe, S., Bouillet, P., Gourraud, J. B., Guicheney, P., Denjoy, I., Redon, R., Mabo, P., le Marec, H., Loussouarn, G., Kyndt, F., Schott, J. J., Probst, V., and Baró, I. (2014) Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations, Basic Res. Cardiol., 109, 446, https://doi.org/10.1007/s00395-014-0446-5.

    Article  CAS  PubMed  Google Scholar 

  9. Portero, V., Le Scouarnec, S., Es-Salah-Lamoureux, Z., Burel, S., Gourraud, J. B., Bonnaud, S., Lindenbaum, P., Simonet, F., Violleau, J., Baron, E., Moreau, E., Scott, C., Chatel, S., Loussouarn, G., O'Hara, T., Mabo, P., Dina, C., Le Marec, H., Schott, J. J., Probst, V., Baró, I., Marionneau, C., Charpentier, F., and Redon, R. (2016) Dysfunction of the voltage-gated K+ channel β2 subunit in a familial case of Brugada syndrome, J. Am Heart Assoc., 5, e003122, https://doi.org/10.1161/JAHA.115.003122.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang, Q. I., Ohno, S., Ding, W. G., Fukuyama, M., Miyamoto, A., Itoh, H., Makiyama, T., Wu, J., Bai, J., Hasegawa, K., Shinohara, T., Takahashi, N., Shimizu, A., Matsuura, H., and Horie, M. (2014) Gain-of-function KCNH2 mutations in patients with Brugada syndrome, J. Cardiovasc. Electrophysiol., 25, 522-530, https://doi.org/10.1111/jce.12361.

    Article  CAS  PubMed  Google Scholar 

  11. Martínez-Barrios, E., Grassi, S., Brión, M., Toro, R., Cesar, S., Cruzalegui, J., Coll, M., Alcalde, M., Brugada, R., Greco, A., Ortega-Sánchez, M. L., Barberia, E., Oliva, A., Sarquella-Brugada, G., and Campuzano, O. (2023) Molecular autopsy: twenty years of post-mortem diagnosis in sudden cardiac death, Front. Med. (Lausanne), 10, 1118585, https://doi.org/10.3389/fmed.2023.1118585.

    Article  PubMed  Google Scholar 

  12. Popa, I. P., Șerban, D. N., Mărănducă, M. A., Șerban, I. L., Tamba, B. I., and Tudorancea, I. (2023) Brugada syndrome: from molecular mechanisms and genetics to risk stratification, Int. J. Mol. Sci., 24, 3328, https://doi.org/10.3390/ijms24043328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., Rehm, H. L., and ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, Genet. Med., 17, 405-424, https://doi.org/10.1038/gim.2015.30.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ten Tusscher, K. H., and Panfilov, A. V. (2006) Alternans and spiral breakup in a human ventricular tissue model, Am. J. Physiol. Heart Circ. Physiol., 291, H1088-H1100, https://doi.org/10.1152/ajpheart.00109.2006.

    Article  CAS  PubMed  Google Scholar 

  15. Hodgkin, A. L., and Huxley, A. F. (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve, J. Physiol., 117, 500, https://doi.org/10.1113/jphysiol.1952.sp004764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Maleckar, M. M., Myklebust, L., Uv, J., Florvaag, P. M., Strøm, V., Glinge, C., Jabbari, R., Vejlstrup, N., Engstrøm, T., Ahtarovski, K., Jespersen, T., Tfelt-Hansen, J., Naumova, V., and Arevalo, H. (2021) Combined in silico and machine learning approaches toward predicting arrhythmic risk in post-infarction patients, Front. Physiol., 12, 745349, https://doi.org/10.3389/fphys.2021.745349.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lopez-Perez, A., Sebastian, R., Izquierdo, M., Ruiz, R., Bishop, M., and Ferrero, J. M. (2019) Personalized cardiac computational models: from clinical data to simulation of infarct-related ventricular tachycardia, Front. Physiol., 10, 580, https://doi.org/10.3389/fphys.2019.00580.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Regazzoni, F., Dedè, L., and Quarteroni, A. (2020) Biophysically detailed mathematical models of multiscale cardiac active mechanics, PLoS Comput. Biol., 16, e1008294, https://doi.org/10.1371/journal.pcbi.1008294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Du, C., Rasmusson, R. L., Bett, G. C., Franks, B., Zhang, H., and Hancox, J. C. (2022) Investigation of the effects of the short QT syndrome D172N Kir2.1 mutation on ventricular action potential profile using dynamic clamp, Front. Pharmacol., 12, 794620, https://doi.org/10.3389/fphar.2021.794620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Karlova, M., Abramochkin, D. V., Pustovit, K. B., Nesterova, T., Novoseletsky, V., Loussouarn, G., Zaklyazminskaya, E., and Sokolova, O. S. (2022) Disruption of a conservative motif in the C-terminal loop of the KCNQ1 channel causes LQT syndrome, Int. J. Mol. Sci., 23, 7953, https://doi.org/10.3390/ijms23147953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Adeniran, I., Whittaker, D. G., El Harchi, A., Hancox, J. C., and Zhang, H. (2017) In silico investigation of a KCNQ1 mutation associated with short QT syndrome, Sci. Rep., 7, 8469, https://doi.org/10.1038/s41598-017-08367-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jeong, D. U., Lee, J., and Lim, K. M. (2020) Computational study to identify the effects of the KCNJ2 E299V mutation in cardiac pum** capacity, Comput. Math. Methods Med., 2020, 7194275, https://doi.org/10.1155/2020/7194275.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ten Tusscher, K. H., Noble, D., Noble, P. J., and Panfilov, A. V. (2004) A model for human ventricular tissue, Am. J. Physiol. Heart Circ. Physiol., 286, H1573-H1589, https://doi.org/10.1152/ajpheart.00794.2003.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou, Z., Gong, Q., Ye, B., Fan, Z., Makielski, J. C., Robertson, G. A., and January, C. T. (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature, Biophys. J., 74, 230-241, https://doi.org/10.1016/S0006-3495(98)77782-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vandenberg, J. I., Varghese, A., Lu, Y., Bursill, J. A., Mahaut-Smith, M. P., and Huang, C. L. H. (2006) Temperature dependence of human ether-a-go-go-related gene K+ currents, Am. J. Physiol. Cell Physiol., 291, C165-C175, https://doi.org/10.1152/ajpcell.00596.2005.

    Article  CAS  PubMed  Google Scholar 

  26. Hindmarsh, A. C., Brown, P. N., Grant, K. E., Lee, S. L., Serban, R., Shumaker, D. E., and Woodward, C. S. (2005) SUNDIALS: suite of nonlinear and differential/algebraic equation solvers, ACM Trans. Math. Softw. TOMS, 31, 363-396, https://doi.org/10.1145/1089014.1089020.

    Article  Google Scholar 

  27. Clerx, M., Collins, P., de Lange, E., and Volders, P. G. (2016) Myokit: a simple interface to cardiac cellular electrophysiology, Prog. Biophys. Mol. Biol., 120, 100-114, https://doi.org/10.1016/j.pbiomolbio.2015.12.008.

    Article  CAS  PubMed  Google Scholar 

  28. R Core Team R: A language and environment for statistical computing. 2015. Available from: https://www.R-project.org/, Accessed April 26, 2023.

  29. Pohlert, T. PMCMRplus: calculate pairwise multiple comparisons of mean rank sums extended. R package version 1.4.0.2018. Available from: https://CRAN.R-project.org/package=PMCMRplus. Accessed April 26, 2023.

  30. Zhang, Y., Dempsey, C. E., and Hancox, J. C. (2020) Electrophysiological characterization of the modified hERGT potassium channel used to obtain the first cryo‐EM hERG structure, Physiol. Rep., 8, e14568, https://doi.org/10.14814/phy2.14568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Malak, O. A., Gluhov, G. S., Grizel, A. V., Kudryashova, K. S., Sokolova, O. S., and Loussouarn, G. (2019) Voltage-dependent activation in EAG channels follows a ligand-receptor rather than a mechanical-lever mechanism, J. Biol. Chem., 294, 6506-6521, https://doi.org/10.1074/jbc.RA119.007626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Alonso-Ron, C., de la Peña, P., Miranda, P., Dominguez, P., and Barros, F. (2008) Thermodynamic and kinetic properties of amino-terminal and S4-S5 loop HERG channel mutants under steady-state conditions, Biophys. J., 94, 3893-3911, https://doi.org/10.1529/biophysj.107.116731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Morita, H., Zipes, D. P., Morita, S. T., and Wu, J. (2007) Differences in arrhythmogenicity between the canine right ventricular outflow tract and anteroinferior right ventricle in a model of BrS, Heart Rhythm, 4, 66-74, https://doi.org/10.1016/j.hrthm.2006.08.030.

    Article  PubMed  Google Scholar 

  34. Antzelevitch, C., Brugada, P., Borggrefe, M., Brugada, J., Brugada, R., Corrado, D., Gussak, I., LeMarec, H., Nademanee, K., Perez Riera, A. R., Shimizu, W., Schulze-Bahr, E., Tan, H., and Wilde, A. (2005) Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association, Circulation, 111, 659-670, https://doi.org/10.1161/01.CIR.0000152479.54298.51.

    Article  PubMed  Google Scholar 

  35. Szél, T., and Antzelevitch, C. (2014) Abnormal repolarization as the basis for late potentials and fractionated electrograms recorded from epicardium in experimental models of Brugada syndrome, J. Am. Coll. Cardiol., 63, 2037-2045, https://doi.org/10.1016/j.jacc.2014.01.067.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Calloe, K., Cordeiro, J. M., Di Diego, J. M., Hansen, R. S., Grunnet, M., Olesen, S. P., and Antzelevitch, C. (2009) A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome, Cardiovasc. Res., 81, 686-694, https://doi.org/10.1093/cvr/cvn339.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Dr. Gildas Loussouarn for fruitful discussions. B.L. and H.Z. acknowledge the Shenzhen Municipal Government and Shenzhen MSU-BIT University support. G.G., B.L., and H.Z. are part of an innovative drug development team based on structural biology and bioinformatics at Shenzhen MSU-BIT University, Guangdong province, P.R.C. (2022KCXTD034).

Funding

The work was supported by the Russian Science Foundation (project no. 22-14-00088).

Author information

Authors and Affiliations

  1. Shenzhen MSU-BIT University, Shenzhen, China

    Denis Abramochkin, Bowen Li, Han Zhang, Grigory Glukhov & Olga S. Sokolova

  2. Lomonosov Moscow State University, 119234, Moscow, Russia

    Denis Abramochkin, Ekaterina Kravchuk, Grigory Glukhov & Olga S. Sokolova

  3. Institute of Immunology and Physiology, Ural Branch of Russian Academy of Sciences, 620049, Ekaterinburg, Russia

    Tatiana Nesterova

  4. Institute of Natural Sciences and Mathematics, Ural Federal University, 620075, Ekaterinburg, Russia

    Tatiana Nesterova

  5. Petrovsky National Research Center of Surgery, 119991, Moscow, Russia

    Anna Shestak & Elena Zaklyazminskaya

Authors
  1. Denis Abramochkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bowen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ekaterina Kravchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tatiana Nesterova
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Grigory Glukhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Shestak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elena Zaklyazminskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Olga S. Sokolova
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

O.S.S. and E.V.Z. conceived and supervised the study; E.V.Z. performed genetic counselling and follow-up of the patient; D.V.A., B.Li, H.Zh., E.K., T.N., G.G., and A.S. carried out molecular biological and electrophysiological experiments; O.S.S., D.V.A., and E.V.Z. discussed the results of experiments with input from all authors; O.S.S. and D.V.A. wrote the manuscript; E.V.Z. and G.G. edited the manuscript.

Corresponding author

Correspondence to Olga S. Sokolova.

Ethics declarations

Clinical and genetic evaluation was performed in accordance with the principles of the Declaration of Helsinki. The authors of this work declare that they have no conflicts of interest.

Additional information

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abramochkin, D., Li, B., Zhang, H. et al. Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening. Biochemistry Moscow 89, 543–552 (2024). https://doi.org/10.1134/S000629792403012X

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S000629792403012X

Keywords

Search

Navigation