Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sodium channel mutations and arrhythmias

Nature Reviews Cardiology volume 6, pages 337–348 (2009)Cite this article

Abstract

Since the identification of the first SCN5A mutation associated with long QT syndrome in 1995, several mutations in this gene for the α subunit of the cardiac sodium channel have been identified in a heterogeneous subset of cardiac rhythm syndromes, including Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation and dilated cardiomyopathy. Robust clinical evidence has been accompanied by bench studies performed in different models spanning from in vitro expression systems to transgenic mice. Together, these studies have helped establish genotype–phenotype correlations and have shaped our understanding of the role of the cardiac sodium channel in health and in disease. Remarkably, these advances in understanding have impacted on clinical management by allowing us to start developing gene-specific risk stratification schemes and mutation-specific management strategies. In this Review, we summarize the current understanding of the molecular mechanism of SCN5A-associated inherited arrhythmias, focusing on the most recent development of mutation-specific management in SCN5A-associated long QT syndrome type 3. We also briefly discuss arrhythmia-causing mutations in the genes encoding the β subunit of the cardiac sodium channel and in those encoding proteins in the associated macromolecular complex.

Key Points

  • The α subunit of the cardiac sodium channel is encoded by the SCN5A gene; most mutations that affect the sodium current in the heart are found in this gene

  • Mutations in the SCN5A gene are associated with long QT syndrome, Brugada syndrome, progressive cardiac conduction defect, sick sinus node syndrome, atrial fibrillation, dilated cardiomyopathy and overlapping syndromes

  • Mutations in genes encoding the β subunit of the cardiac sodium channel and in those encoding proteins in the associated macromolecular complex can also cause arrhythmias

  • The biophysical characterization of SCN5A mutations allows us to explain, at least in part, the clinical phenotypes observed in patients

  • A gene-specific approach is required for risk stratification and treatment of patients with long QT syndrome type 3

  • In vitro studies of SCN5A mutations have identified sets of biophysical properties that might be used to predict patients' responses to therapy

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The ventricular action potential.
Figure 2: Schematic representation of SCN5A-encoded protein, with localization of the mutations and associated phenotypes.
Figure 3: Schematic representation of the cardiac sodium channel macromolecular complex.
Figure 4: Ensemble average of single-channel recordings from a | wild-type and b | ΔKPQ sodium channels in inside-out membrane patches excised from Xenopus oocytes during 200 ms duration voltage-clamp steps.
Figure 5: Steady-state inactivation and window current.
Figure 6: A four-generation family with the SCN5A mutation ΔK1500 exhibited long QT syndrome, Brugada syndrome and conduction system disease.
Figure 7: A hyperpolarizing shift of inactivation might be associated with good clinical response to mexiletine.
Figure 8: Gene-centered classification of inherited arrhythmogenic diseases.

Similar content being viewed by others

References

  1. Wang, Q. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995).

    Article  CAS  Google Scholar 

  2. Inherited Arrhythmias Database. [online January 2000] http://www.fsm.it/cardmoc/ (accessed 25 February 2009).

  3. Chen, Q. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nat. 392, 293–296 (1998).

    Article  CAS  Google Scholar 

  4. Schott, J. J. et al. Cardiac conduction defects associate with mutations in SCN5A. Nature Genet. 23, 20–21 (1999).

    Article  CAS  Google Scholar 

  5. Benson, D. W. et al. Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J. Clin. Invest. 112, 1019–1028 (2003).

    Article  CAS  Google Scholar 

  6. Makiyama, T. et al. A novel SCN5A gain-of-function mutation M1875T associated with familial atrial fibrillation. J. Am. Coll. Cardiol. 52, 1326–1334 (2008).

    Article  CAS  Google Scholar 

  7. Bezzina, C. R. et al. Compound heterozygosity for mutations (W156X and R225W) in SCN5A associated with severe cardiac conduction disturbances and degenerative changes in the conduction system. Circ. Res. 92, 159–168 (2003).

    Article  CAS  Google Scholar 

  8. Napolitano, C., Rivolta, I. & Priori, S. G. Cardiac sodium channel diseases. Clin. Chem. Lab. Med. 41, 439–444 (2003).

    Article  CAS  Google Scholar 

  9. George, A. L. Jr. Inherited disorders of voltage-gated sodium channels. J. Clin. Invest. 115, 1990–1999 (2005).

    Article  CAS  Google Scholar 

  10. Clancy, C. E. & Kass, R. S. Inherited and acquired vulnerability to ventricular arrhythmias: cardiac Na+ and K+ channels. Physiol. Rev. 85, 33–47 (2005).

    Article  CAS  Google Scholar 

  11. Kass, R. S. & Moss, A. J. Mutation-specific pharmacology of the long QT syndrome. Handb. Exp. Pharmacol. 171, 287–304 (2006).

    Article  CAS  Google Scholar 

  12. Napolitano, C., Bloise, R. & Priori, S. G. Gene-specific therapy for inherited arrhythmogenic diseases. Pharmacol. Ther. 110, 1–13 (2006).

    Article  CAS  Google Scholar 

  13. Balser, J. R. The cardiac sodium channel: gating function and molecular pharmacology. J. Mol. Cell Cardiol. 33, 599–613 (2001).

    Article  CAS  Google Scholar 

  14. Watanabe, H. et al. Sodium channel beta1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J. Clin. Invest. 118, 2260–2268 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Medeiros-Domingo, A. et al. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation 116, 134–142 (2007).

    Article  Google Scholar 

  16. Abriel, H. & Kass, R. S. Regulation of the voltage-gated cardiac sodium channel Nav1.5 by interacting proteins. Trends Cardiovasc. Med. 15, 35–40 (2005).

    Article  CAS  Google Scholar 

  17. Napolitano, C. et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA 294, 2975–2980 (2005).

    Article  CAS  Google Scholar 

  18. Splawski, I. et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102, 1178–1185 (2000).

    Article  CAS  Google Scholar 

  19. Priori, S. G. et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 292, 1341–1344 (2004).

    Article  CAS  Google Scholar 

  20. Bennett, P. B., Yazawa, K., Makita, N. & George, A. L. Jr . Molecular mechanism for an inherited cardiac arrhythmia. Nature 376, 683–685 (1995).

    Article  CAS  Google Scholar 

  21. Wang, D. W., Yazawa, K., George, A. L. Jr & Bennett, P. B. Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome. Proc. Natl Acad. Sci. USA 93, 13200–13205 (1996).

    Article  CAS  Google Scholar 

  22. Clancy, C. E., Tateyama, M., Liu, H., Wehrens, X. H. & Kass, R. S. Non-equilibrium gating in cardiac Na+ channels: an original mechanism of arrhythmia. Circulation 107, 2233–2237 (2003).

    Article  CAS  Google Scholar 

  23. Nuyens, D. et al. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat. Med. 7, 1021–1027 (2001).

    Article  CAS  Google Scholar 

  24. Fabritz, L. et al. Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice. Cardiovasc. Res. 57, 1085–1093 (2003).

    Article  CAS  Google Scholar 

  25. Tian, X. L. et al. Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo. Cardiovasc. Res. 61, 256–267 (2004).

    Article  CAS  Google Scholar 

  26. Brugada, P. & Brugada, J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J. Am. Coll. Cardiol. 20, 1391–1396 (1992).

    Article  CAS  Google Scholar 

  27. Bai, R. et al. Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing. Circ. Arrhythmia Electrophysiol. 2, 6–15 (2009).

    Article  CAS  Google Scholar 

  28. Antzelevitch, C. et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 111, 659–670 (2005).

    Article  Google Scholar 

  29. Deschenes, I. et al. Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes. Cardiovasc. Res. 46, 55–65 (2000).

    Article  CAS  Google Scholar 

  30. Valdivia, C. R. et al. A novel SCN5A arrhythmia mutation, M1766L, with expression defect rescued by mexiletine. Cardiovasc. Res. 55, 279–289 (2002).

    Article  CAS  Google Scholar 

  31. Valdivia, C. R. et al. A trafficking defective, Brugada syndrome-causing SCN5A mutation rescued by drugs. Cardiovasc. Res. 62, 53–62 (2004).

    Article  CAS  Google Scholar 

  32. Pfahnl, A. E. et al. A sodium channel pore mutation causing Brugada syndrome. Heart Rhythm 4, 46–53 (2007).

    Article  Google Scholar 

  33. Herfst, L. J., Rook, M. B. & Jongsma, H. J. Trafficking and functional expression of cardiac Na+ channels. J. Mol. Cell Cardiol. 36, 185–193 (2004).

    Article  CAS  Google Scholar 

  34. Bezzina, C. R. & Tan, H. L. Pharmacological rescue of mutant ion channels. Cardiovasc. Res. 55, 229–232 (2002).

    Article  CAS  Google Scholar 

  35. Rivolta, I. et al. Inherited Brugada and long QT-3 syndrome mutations of a single residue of the cardiac sodium channel confer distinct channel and clinical phenotypes. J. Biol. Chem. 276, 30623–30630 (2001).

    Article  CAS  Google Scholar 

  36. Baroudi, G., Carbonneau, E., Pouliot, V. & Chahine, M. SCN5A mutation (T1620M) causing Brugada syndrome exhibits different phenotypes when expressed in Xenopus oocytes and mammalian cells. FEBS Lett. 467, 12–16 (2000).

    Article  CAS  Google Scholar 

  37. Wang, D. W., Makita, N., Kitabatake, A., Balser, J. R. & George, A. L. Jr. Enhanced Na+ channel intermediate inactivation in Brugada syndrome. Circ. Res. 87, E37–E43 (2000).

    Article  CAS  Google Scholar 

  38. Grant, A. O. Electrophysiological basis and genetics of Brugada syndrome. J. Cardiovasc. Electrophysiol. 16 (Suppl. 1), S3–S7 (2005).

    Article  Google Scholar 

  39. Yan, G. X. & Antzelevitch, C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 100, 1660–1666 (1999).

    Article  CAS  Google Scholar 

  40. Antzelevitch, C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 4, 964–972 (2007).

    Article  Google Scholar 

  41. Coronel, R. et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation 112, 2769–2777 (2005).

    Article  Google Scholar 

  42. Remme, C. A. et al. Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD. Circulation 114, 2584–2594 (2006).

    Article  CAS  Google Scholar 

  43. Stokoe, K. S. et al. Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a± murine hearts modelling the Brugada syndrome. J. Physiol. 581, 255–275 (2007).

    Article  CAS  Google Scholar 

  44. Wang, D. W., Viswanathan, P. C., Balser, J. R., George, A. L. Jr & Benson, D. W. Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block. Circulation 105, 341–346 (2002).

    Article  CAS  Google Scholar 

  45. Tan, H. L. et al. A sodium-channel mutation causes isolated cardiac conduction disease. Nature 409, 1043–1047 (2001).

    Article  CAS  Google Scholar 

  46. Kyndt, F. et al. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 104, 3081–3086 (2001).

    Article  CAS  Google Scholar 

  47. Shirai, N. et al. A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease. Cardiovasc. Res. 53, 348–354 (2002).

    Article  CAS  Google Scholar 

  48. Papadatos, G. A. et al. Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene SCN5A. Proc. Natl Acad. Sci. USA 99, 6210–6215 (2002).

    Article  CAS  Google Scholar 

  49. Royer, A. et al. Mouse model of SCN5A-linked hereditary Lenegre's disease: age-related conduction slowing and myocardial fibrosis. Circulation 111, 1738–1746 (2005).

    Article  CAS  Google Scholar 

  50. Smits, J. P. et al. A mutation in the human cardiac sodium channel (E161K) contributes to sick sinus syndrome, conduction disease and Brugada syndrome in two families. J. Mol. Cell Cardiol. 38, 969–981 (2005).

    Article  CAS  Google Scholar 

  51. Lei, M. Zhang, H., Grace, A. A. & Huang, C. L. SCN5A and sinoatrial node pacemaker function. Cardiovasc. Res. 74, 356–365 (2007).

    Article  CAS  Google Scholar 

  52. Olson, T. M. & Keating, M. T. Mapping a cardiomyopathy locus to chromosome 3p22-p25. J. Clin. Invest. 97, 528–532 (1996).

    Article  CAS  Google Scholar 

  53. Ge, J. et al. Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy. Circ. Arrhythmia Electrophysiol. 1, 83–92 (2008).

    Article  CAS  Google Scholar 

  54. Shi, R. et al. The cardiac sodium channel mutation delQKP 1507–1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death. Europace 10, 1329–1335 (2008).

    Article  Google Scholar 

  55. Letsas, K. P. et al. Prevalence of paroxysmal atrial fibrillation in Brugada syndrome: a case series and a review of the literature. J. Cardiovasc. Med. (Hagerstown) 8, 803–806 (2007).

    Article  Google Scholar 

  56. Bezzina, C. et al. A single Na+ channel mutation causing both long-QT and Brugada syndromes. Circ. Res. 85, 1206–1213 (1999).

    Article  CAS  Google Scholar 

  57. Grant, A. O. et al. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J. Clin. Invest. 110, 1201–1209 (2002).

    Article  CAS  Google Scholar 

  58. Priori, S. G. et al. The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation 102, 945–947 (2000).

    Article  CAS  Google Scholar 

  59. Wei, J. et al. Congenital long-QT syndrome caused by a novel mutation in a conserved acidic domain of the cardiac Na+ channel. Circulation 99, 3165–3171 (1999).

    Article  CAS  Google Scholar 

  60. Priori, S. G. et al. Natural history of Brugada syndrome: insights for risk stratification and management. Circulation 105, 1342–1347 (2002).

    Article  Google Scholar 

  61. Makita, N. et al. The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome. J. Clin. Invest. 118, 2219–2229 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Remme, C. A. & Wilde, A. A. SCN5A overlap syndromes: no end to disease complexity? Europace 10, 1253–1255 (2008).

    Article  Google Scholar 

  63. Priori, S. G. Inherited arrhythmogenic diseases: the complexity beyond monogenic disorders. Circ. Res. 94, 140–145 (2004).

    Article  CAS  Google Scholar 

  64. Priori, S. G. et al. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: a prospective evaluation of 52 families. Circulation 102, 2509–2515 (2000).

    Article  CAS  Google Scholar 

  65. Mohler, P. J. et al. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc. Natl Acad. Sci. USA 101, 17533–17538 (2004).

    Article  CAS  Google Scholar 

  66. Vatta, M. et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114, 2104–2112 (2006).

    Article  CAS  Google Scholar 

  67. Ueda, K. et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc. Natl Acad. Sci. USA 105, 9355–9360 (2008).

    Article  CAS  Google Scholar 

  68. London, B. et al. Mutation in glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation 116, 2260–2268 (2007).

    Article  CAS  Google Scholar 

  69. Zipes, D. P. et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 114, e385–e484 (2006).

    Article  Google Scholar 

  70. Schwartz, P. J. et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Circulation 92, 3381–3386 (1995).

    Article  CAS  Google Scholar 

  71. Chang, C. C. et al. A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia. Cardiovasc. Res. 64, 268–278 (2004).

    Article  CAS  Google Scholar 

  72. Kambouris, N. G. et al. Phenotypic characterization of a novel long-QT syndrome mutation (R1623Q) in the cardiac sodium channel. Circulation 97, 640–644 (1998).

    Article  CAS  Google Scholar 

  73. Benhorin, J. et al. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation 101, 1698–1706 (2000).

    Article  CAS  Google Scholar 

  74. Abriel, H., Wehrens, X. H., Benhorin, J., Kerem, B. & Kass, R. S. Molecular pharmacology of the sodium channel mutation D1790G linked to the long-QT syndrome. Circulation 102, 921–925 (2000).

    Article  CAS  Google Scholar 

  75. Ruan, Y., Liu, N., Bloise, R., Napolitano, C. & Priori, S. G. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation 116, 1137–1144 (2007).

    Article  CAS  Google Scholar 

  76. Priori, S. G. et al. Genetics of Long QT, Brugada and other channelopathies. In Cardiac Electrophysiology (eds Zipes, D. P. et al.) 462–470 (Elsevier, Philadelphia, 2003).

    Google Scholar 

  77. Makiyama, T. et al. High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J. Am. Coll. Cardiol. 46, 2100–2106 (2005).

    Article  CAS  Google Scholar 

  78. Makita, N. et al. Congenital atrial standstill associated with coinheritance of a novel SCN5A mutation and connexin 40 polymorphisms. Heart Rhythm 2, 1128–1134 (2005).

    Article  Google Scholar 

  79. Takehara, N. et al. A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill. J. Intern. Med. 255, 137–142 (2004).

    Article  CAS  Google Scholar 

  80. Zhang, Y. et al. Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel. Acta Physiol. (Oxf.) 194, 311–323 (2008).

    Article  CAS  Google Scholar 

  81. Tan, B. H. et al. A novel C-terminal truncation SCN5A mutation from a patient with sick sinus syndrome, conduction disorder and ventricular tachycardia. Cardiovasc. Res. 76, 409–417 (2007).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA

    Yanfei Ruan, Nian Liu & Silvia G. Priori

  2. Department of Cardiology, Molecular Cardiology Fondazione Salvatore Maugeri, University of Pavia, Pavia, Italy

    Silvia G. Priori

Authors
  1. Yanfei Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia G. Priori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Silvia G. Priori.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruan, Y., Liu, N. & Priori, S. Sodium channel mutations and arrhythmias. Nat Rev Cardiol 6, 337–348 (2009). https://doi.org/10.1038/nrcardio.2009.44

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2009.44

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing