Advertisement

Novel SCN5A mutations in two families with “Brugada-like” ST elevation in the inferior leads and conduction disturbances

  • Philippe MauryEmail author
  • Adrien Moreau
  • Francoise Hidden-Lucet
  • Antoine Leenhardt
  • Veronique Fressart
  • Myriam Berthet
  • Isabelle Denjoy
  • Nawal Bennamar
  • Anne Rollin
  • Christelle Cardin
  • Pascale Guicheney
  • Mohamed Chahine
Article

Abstract

Aims

Brugada syndrome (BrS) is an inherited cardiac disease characterized by ST segment elevation in V1–V3 ECG leads. Mutations SCN5A gene encoding for the cardiac voltage-gated Na+ channel are found in some BrS patients, but also in family members with isolated conduction disturbances. However, some patients show coved ST elevation in the inferior or lateral leads whose association with SCN5A and familial conduction disturbances are poorly known.

Methods and results

Two novel SCN5A mutations, D1430N and Q1476X, were identified in two unrelated families comprising patients with Brugada-like ST elevation located in the inferior leads or isolated conduction disturbances. Wild-type (WT) and D1430N mutant channels were expressed in tsA201 cells. Patch clamp electrophysiological experiments revealed total absence of Na+ current resulting from Nav1.5 mutant when compared to WT channels. Treatments known to restore trafficking defect (incubation at low temperature, with mexiletine or lidocaine) did not restore Na+ current supporting that Nav1.5 mutation is not a defective trafficking mutation. Furthermore, immunocytolabelling indicates the membrane localisation of both WT and mutant channels confirming what we observed in our patch clamp experiments. This suggests that the mutation may induce a complete block of Na+ permeation. The nonsense mutation Q1476X was leading to a premature stop codon and was not expressed.

Conclusion

Brugada-like ST elevation in the inferior ECG leads or isolated conduction disturbances were found in two unrelated families and associated with two novel SCN5A mutations. The missense and nonsense mutations are both resulting in a complete loss of ventricular Na+ current explaining the phenotypes.

Keywords

Brugada ST elevation Conduction disturbance Overlap syndrome SCN5A 

References

  1. 1.
    Antzelevitch, C., Brugada, P., Borggrefe, M., Brugada, J., Brugada, R., Corrado, D., et al. (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.PubMedCrossRefGoogle Scholar
  2. 2.
    Potet, F., Mabo, P., Le Coq, G., Probst, V., Schott, J. J., Airaud, F., et al. (2003). Novel brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads. Journal of Cardiovascular Electrophysiology, 14, 200–203.PubMedCrossRefGoogle Scholar
  3. 3.
    Riera, A. R., Ferreira, C., Schapachnik, E., Sanches, P. C., & Moffa, P. J. (2004). Brugada syndrome with atypical ECG: downsloping ST-segment elevation in inferior leads. J Electrocardiol, 37, 101–104.PubMedCrossRefGoogle Scholar
  4. 4.
    Lombardi, F., Potenza, S., Beltrami, A., Verzoni, A., Brugada, P., & Brugada, R. (2007). Simultaneous ST-segment elevation in the right precordial and inferior leads in Brugada syndrome. Journal of Cardiovascular Medicine (Hagerstown, Md.), 8, 201–204.CrossRefGoogle Scholar
  5. 5.
    Van den Berg, M. P., & Wiesfeld, A. C. (2006). Brugada syndrome with ST-segment elevation in the lateral leads. Journal of Cardiovascular Electrophysiology, 17, 1035.PubMedCrossRefGoogle Scholar
  6. 6.
    Bonakdar, H., Haghjoo, M., & Sadr-Ameli, M. A. (2008). Brugada syndrome manifested by the typical electrocardiographic pattern both in the right precordial and the high lateral leads. Indian Pacing Electrophysiol J, 8, 137–140.PubMedGoogle Scholar
  7. 7.
    Kawamura, M., Ozawa, T., Yao, T., Ashihara, T., Sugimoto, Y., Yagi, T., et al. (2009). Dynamic change in ST-segment and spontaneous occurrence of ventricular fibrillation in Brugada syndrome with a novel nonsense mutation in the SCN5A gene during long-term follow-up. Circulation Journal, 73, 584–588.PubMedCrossRefGoogle Scholar
  8. 8.
    Sassone, B., Sacca, S., & Donateo, M. (2006). Paradoxical effect of ajmaline in a patient with Brugada syndrome. Europace, 8, 251–254.PubMedCrossRefGoogle Scholar
  9. 9.
    Porres, J. M., Brugada, J., Urbistondo, V., García, F., Reviejo, K., & Marco, P. (2002). Fever unmasking the Brugada syndrome. Pacing and Clinical Electrophysiology, 25, 1646–1648.PubMedCrossRefGoogle Scholar
  10. 10.
    Sarkozy, A., Chierchia, G. B., Paparella, G., Boussy, T., De Asmundis, C., Roos, M., et al. (2009). Inferior and lateral electrocardiographic repolarization abnormalities in Brugada syndrome. Circulation. Arrhythmia and Electrophysiology, 2, 154–161.PubMedCrossRefGoogle Scholar
  11. 11.
    Batchvarov, V. N., Govindan, M., Camm, A. J., & Behr, E. R. (2009). Brugada-like changes in the peripheral leads during diagnostic ajmaline test in patients with suspected Brugada syndrome. Pacing and Clinical Electrophysiology, 32, 695–703.PubMedCrossRefGoogle Scholar
  12. 12.
    Kapplinger, J. D., Tester, D. J., Alders, M., Benito, B., Berthet, M., Brugada, J., et al. (2010). An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm, 7, 33–46.PubMedCrossRefGoogle Scholar
  13. 13.
    Baroudi, G., Pouliot, V., Denjoy, I., Guicheney, P., Shrier, A., & Chahine, M. (2001). Novel mechanism for Brugada syndrome: defective surface localization of an SCN5A mutant (R1432G). Circulation Research, 88, E78–83.PubMedCrossRefGoogle Scholar
  14. 14.
    Valdivia, C. R., Tester, D. J., Rok, B. A., Porter, C. B., Munger, T. M., Jahangir, A., et al. (2004). A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovascular Research, 62, 53–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Jiang, C., Atkinson, D., Towbin, J. A., Splawski, I., Lehmann, M. H., Li, H., et al. (1994). Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nature Genetics, 8, 141–147.PubMedCrossRefGoogle Scholar
  16. 16.
    Schott, J. J., Alshinawi, C., Kyndt, F., Probst, V., Hoorntje, T. M., Hulsbeek, M., et al. (1999). Cardiac conduction defects associate with mutations in SCN5A. Nature Genetics, 23, 20–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Tan, H. L., Bink-Boelkens, M. T., Bezzina, C. R., Viswanathan, P. C., Beaufort-Krol, G. C., van Tintelen, P. J., et al. (2001). A sodium-channel mutation causes isolated cardiac conduction disease. Nature, 409, 1043–1047.PubMedCrossRefGoogle Scholar
  18. 18.
    Huang, H., Priori, S. G., Napolitano, C., O'Leary, M. E., & Chahine, M. (2011). Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels. American Journal of Physiology. Heart and Circulatory Physiology, 300, H288–299.PubMedCrossRefGoogle Scholar
  19. 19.
    Deschênes, I., Baroudi, G., Berthet, M., Barde, I., Chalvidan, T., Denjoy, I., et al. (2000). Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes. Cardiovascular Research, 46, 55–65.PubMedCrossRefGoogle Scholar
  20. 20.
    Teng, S., Gao, L., Paajanen, V., Pu, J., & Fan, Z. (2009). Readthrough of nonsense mutation W822X in the SCN5A gene can effectively restore expression of cardiac Na+ channels. Cardiovascular Research, 83, 473–480.PubMedCrossRefGoogle Scholar
  21. 21.
    Baroudi, G., Napolitano, C., Priori, S. G., Del Bufalo, A., & Chahine, M. (2004). Loss of function associated with novel mutations of the SCN5A gene in patients with Brugada syndrome. The Canadian Journal of Cardiology, 20, 425–430.PubMedGoogle Scholar
  22. 22.
    Keller, D. I., Rougier, J. S., Kucera, J. P., Benammar, N., Fressart, V., Guicheney, P., et al. (2005). Brugada syndrome and fever: genetic and molecular characterization of patients carrying SCN5A mutations. Cardiovascular Research, 67, 510–519.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhao, J., Ziane, R., Chatelier, A., O'Leary, M. E., & Chahine, M. (2007). Lidocaine promotes the trafficking and functional expression of Na(v)1.8 sodium channels in mammalian cells. Journal of Neurophysiology, 98, 467–477.PubMedCrossRefGoogle Scholar
  24. 24.
    Kyndt, F., Probst, V., Potet, F., Demolombe, S., Chevallier, J. C., Baro, I., et al. (2001). Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation, 104, 3081–3086.PubMedCrossRefGoogle Scholar
  25. 25.
    Six, I., Hermida, J. S., Huang, H., Gouas, L., Fressart, V., Benammar, N., et al. (2008). The occurrence of Brugada syndrome and isolated cardiac conductive disease in the same family could be due to a single SCN5A mutation or to the accidental association of both diseases. Europace, 10, 79–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Makiyama, T., Akao, M., Tsuji, K., Doi, T., Ohno, S., Takenaka, K., et al. (2005). High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. Journal of the American College of Cardiology, 46, 2100–2106.PubMedCrossRefGoogle Scholar
  27. 27.
    Vatta, M., Dumaine, R., Varghese, G., Richard, T. A., Shimizu, W., Aihara, N., et al. (2002). Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Human Molecular Genetics, 11, 337–345.PubMedCrossRefGoogle Scholar
  28. 28.
    Zhang, Y., Wang, T., Ma, A., Zhou, X., Gui, J., Wan, H., et al. (2008). Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel. Acta Physiologica (Oxford, England), 194, 311–323.CrossRefGoogle Scholar
  29. 29.
    Zimmer, T., Biskup, C., Dugarmaa, S., Vogel, F., Steinbis, M., Böhle, T., et al. (2002). Functional expression of GFP-linked human heart sodium channel (hH1) and subcellular localization of the a subunit in HEK293 cells and dog cardiac myocytes. Journal of Membrane Biology, 186, 1–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Antzelevitch C, Fish JM, Di Diego JM. (2007) Cellular mechanisms underlying the brugada syndrome. In C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada (Eds.), The brugada syndrome: from bench to bedside (pp. 52–77). Oxford: Blackwell Science Ltd.Google Scholar
  31. 31.
    Perez Riera AR, Ferreira C, Schapachnik E. (2007) Value of 12 lead electrocardiogram and derived methodologies in the diagnosis of Brugada disease. In C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada (Eds.), The Brugada syndrome: from bench to bedside (pp. 87–110). Oxford: Blackwell Science Ltd.Google Scholar
  32. 32.
    Shu, J., Zhu, T., Yang, L., Cui, C., & Yan, G. X. (2005). ST-segment elevation in the early repolarization syndrome, idiopathic ventricular fibrillation, and the Brugada syndrome: cellular and clinical linkage. Journal of Electrocardiology, 38(4 Suppl), 26–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Wichter, T., Matheja, P., Eckardt, L., Kies, P., Schäfers, K., Schulze-Bahr, E., et al. (2002). Cardiac autonomic dysfunction in Brugada syndrome. Circulation, 105, 702–706.PubMedCrossRefGoogle Scholar
  34. 34.
    Meregalli, P. G., Wilde, A. A., & Tan, H. L. (2005). Pathophysiological mechanisms of Brugada syndrome: depolarization disorder, repolarization disorder, or more? Cardiovascular Research, 67, 367–378.PubMedCrossRefGoogle Scholar
  35. 35.
    Probst, V., Allouis, M., Sacher, F., Pattier, S., Babuty, D., Mabo, P., et al. (2006). Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation. Journal of Cardiovascular Electrophysiology, 17, 270–275.PubMedCrossRefGoogle Scholar
  36. 36.
    Rossenbacker, T., Carroll, S. J., Liu, H., Kuipéri, C., de Ravel, T. J., Devriendt, K., et al. (2004). Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death. Heart Rhythm, 1, 610–615.PubMedCrossRefGoogle Scholar
  37. 37.
    Smits, J. P., Koopmann, T. T., Wilders, R., Veldkamp, M. W., Opthof, T., Bhuiyan, Z. A., et al. (2005). A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. Journal of Molecular and Cellular Cardiology, 38, 969–981.PubMedCrossRefGoogle Scholar
  38. 38.
    Postema, P. G., Van den Berg, M., Van Tintelen, J. P., Van den Heuvel, F., Grundeken, M., Hofman, N., et al. (2009). Founder mutations in the Netherlands: SCN5a 1795insD, the first described arrhythmia overlap syndrome and one of the largest and best characterised families worldwide. Neth Heart J, 17, 422–428.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Philippe Maury
    • 1
    Email author
  • Adrien Moreau
    • 2
    • 3
  • Francoise Hidden-Lucet
    • 4
    • 5
    • 6
  • Antoine Leenhardt
    • 7
    • 8
    • 9
  • Veronique Fressart
    • 10
  • Myriam Berthet
    • 5
    • 6
  • Isabelle Denjoy
    • 5
    • 6
    • 7
  • Nawal Bennamar
    • 10
  • Anne Rollin
    • 1
  • Christelle Cardin
    • 1
  • Pascale Guicheney
    • 5
    • 6
  • Mohamed Chahine
    • 2
    • 3
  1. 1.Unité de Rythmologie et de Stimulation Cardiaque, Fédération de CardiologieUniversity Hospital RangueilToulouseFrance
  2. 2.Centre de recherche de l’institut universitaire de santé mentale de QuébecQuebec CityCanada
  3. 3.Department of MedicineUniversité LavalQuebec CityCanada
  4. 4.AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Rythmologie, et Centre de Référence des Maladies Cardiaques HéréditairesParisFrance
  5. 5.Inserm, U956, Faculté de Médecine Pierre et Marie Curie, site Pitié-SalpêtrièreParisFrance
  6. 6.Université Pierre et Marie CurieUniv Paris 06, UMR_S956ParisFrance
  7. 7.AP-HP, Hôpital Bichat, Service de Cardiologie et Centre de Référence des Maladies Cardiaques HéréditairesParisFrance
  8. 8.Inserm, U942, Hôpital LariboisièreParisFrance
  9. 9.Université Paris DiderotParisFrance
  10. 10.AP-HP, Groupe Hospitalier Pitié-Salpétrière, Service de Biochimie Métabolique, UF Cardiogénétique et Myogénétique Moléculaire et CellulaireParisFrance

Personalised recommendations