Novel SCN5A mutations in two families with “Brugada-like” ST elevation in the inferior leads and conduction disturbances
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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.
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.
KeywordsBrugada ST elevation Conduction disturbance Overlap syndrome SCN5A
- 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
- 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
- 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
- 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.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.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
- 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.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.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