© 1999 American Heart Association, Inc.
Clinical Research |
A Single Na+ Channel Mutation Causing Both Long-QT and Brugada Syndromes
From the Departments of Clinical Genetics (C.B., A.V.P., I.M.v.L, M.M.A.M.M.) and Experimental and Molecular Cardiology (C.B., A.V.P., M.W.V., A.A.M.W.), Academic Medical Center, Amsterdam; Departments of Cardiology (M.P.v.d.B, J.-W.V.), Medical Genetics (G.T.-S., A.H.v.d.H.), and Paediatrics (M.Th.E.B.-B.), Groningen University Hospital, Groningen; Departments of Medical Physiology (M.B.R.) and Cardiology (A.A.M.W.), Utrecht University Hospital, Utrecht, the Netherlands; and the Interuniversity Cardiology Institute of the Netherlands (A.A.M.W.).
Correspondence to Dr A.A.M. Wilde, Department of Clinical and Experimental Cardiology, AMC, PO Box 22700, 1100 DE Amsterdam, the Netherlands. E-mail a.a.wilde{at}amc.uva.nl
Abstract—Mutations in SCN5A, the gene encoding the cardiac Na+ channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT3) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the "Brugada ECG" occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, n=43; noncarriers, n=36). In affected individuals, PR and QRS durations and QT intervals are prolonged (P<0.0001 for all parameters). ST segment elevation in the right precordial leads is present as well (P<0.0001). Twenty-five family members died suddenly, 16 of them during the night. Expression of wild-type and mutant Na+ channels in Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV negative shift of the steady-state inactivation curve and an 8.1-mV positive shift of the steady-state activation curve. The functional consequence of both shifts is likely to be a reduced Na+ current during the upstroke of the action potential. LQT3 and Brugada syndrome are allelic disorders but may also share a common genotype.
Key Words: long-QT syndrome • Brugada syndrome • SCN5A • arrhythmia • Na+ channel
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N. Shirai, N. Makita, K. Sasaki, H. Yokoi, I. Sakuma, H. Sakurada, J. Akai, A. Kimura, M. Hiraoka, and A. Kitabatake A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease Cardiovasc Res, February 1, 2002; 53(2): 348 - 354. [Abstract] [Full Text] [PDF]
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R. Brugada and R. Roberts Brugada Syndrome: Why Are There Multiple Answers to a Simple Question? Circulation, December 18, 2001; 104(25): 3017 - 3019. [Full Text] [PDF]
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F. Kyndt, V. Probst, F. Potet, S. Demolombe, J.-C. Chevallier, I. Baro, J.-P. Moisan, P. Boisseau, J.-J. Schott, D. Escande, et al. Novel SCN5A Mutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family Circulation, December 18, 2001; 104(25): 3081 - 3086. [Abstract] [Full Text] [PDF]
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S Sangwatanaroj, S Prechawat, B Sunsaneewitayakul, S Sitthisook, P Tosukhowong, and K Tungsanga New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives Eur. Heart J., December 2, 2001; 22(24): 2290 - 2296. [Abstract] [PDF]
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P Syrris, A Murray, N D Carter, W M McKenna, and S Jeffery Mutation detection in long QT syndrome: a comprehensive set of primers and PCR conditions J. Med. Genet., October 1, 2001; 38(10): 705 - 710. [Full Text] [PDF]
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P. C. Viswanathan, C. R. Bezzina, A. L. George Jr., D. M. Roden, A. A.M. Wilde, and J. R. Balser Gating-Dependent Mechanisms for Flecainide Action in SCN5A-Linked Arrhythmia Syndromes Circulation, September 4, 2001; 104(10): 1200 - 1205. [Abstract] [Full Text] [PDF]
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P. M. Spooner, C. Albert, E. J. Benjamin, R. Boineau, R. C. Elston, A. L. George Jr, X. Jouven, L. H. Kuller, J. W. MacCluer, E. Marban, et al. Sudden Cardiac Death, Genes, and Arrhythmogenesis : Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part I Circulation, May 15, 2001; 103(19): 2361 - 2364. [Abstract] [Full Text] [PDF]
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I. Gussak, P. Bjerregaard, and S. C. Hammill Clinical diagnosis and risk stratification in patients with brugada syndrome J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1635 - 1638. [Full Text] [PDF]
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C Antzelevitch The Brugada syndrome: diagnostic criteria and cellular mechanisms Eur. Heart J., March 1, 2001; 22(5): 356 - 363. [PDF]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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X. Wan, S. Chen, A. Sadeghpour, Q. Wang, and G. E. Kirsch Accelerated inactivation in a mutant Na+ channel associated with idiopathic ventricular fibrillation Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H354 - H360. [Abstract] [Full Text] [PDF]
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D. W. Wang, N. Makita, A. Kitabatake, J. R. Balser, and A. L. George Jr Enhanced Na+ Channel Intermediate Inactivation in Brugada Syndrome Circ. Res., October 13, 2000; 87 (8): e37 - e43. [Abstract] [Full Text] [PDF]
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I. Splawski, J. Shen, K. W. Timothy, M. H. Lehmann, S. Priori, J. L. Robinson, A. J. Moss, P. J. Schwartz, J. A. Towbin, G. M. Vincent, et al. Spectrum of Mutations in Long-QT Syndrome Genes : KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 Circulation, September 5, 2000; 102(10): 1178 - 1185. [Abstract] [Full Text] [PDF]
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S. G. Priori, C. Napolitano, P. J. Schwartz, R. Bloise, L. Crotti, and E. Ronchetti The Elusive Link Between LQT3 and Brugada Syndrome : The Role of Flecainide Challenge Circulation, August 29, 2000; 102(9): 945 - 947. [Abstract] [Full Text] [PDF]
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H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]
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C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]
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M. W. Veldkamp, P. C. Viswanathan, C. Bezzina, A. Baartscheer, A. A. M. Wilde, and J. R. Balser Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na+ Channel Circ. Res., May 12, 2000; 86 (9): e91 - e97. [Abstract] [Full Text] [PDF]
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A. A.M. Wilde and M. W. Veldkamp What we can learn from individual resuscitated patients Cardiovasc Res, April 1, 2000; 46(1): 14 - 16. [Full Text] [PDF]
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I. Rivolta, H. Abriel, M. Tateyama, H. Liu, M. Memmi, P. Vardas, C. Napolitano, S. G. Priori, and R. S. Kass 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., August 10, 2001; 276(33): 30623 - 30630. [Abstract] [Full Text] [PDF]
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H. Abriel, C. Cabo, X. H. T. Wehrens, I. Rivolta, H. K. Motoike, M. Memmi, C. Napolitano, S. G. Priori, and R. S. Kass Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel Circ. Res., April 13, 2001; 88(7): 740 - 745. [Abstract] [Full Text] [PDF]
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C. E. Clancy and Y. Rudy Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Circulation, March 12, 2002; 105(10): 1208 - 1213. [Abstract] [Full Text] [PDF]
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