This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Probst, V. Articles by Le Marec, H. Search for Related Content PubMed PubMed Citation Articles by Probst, V. Articles by Le Marec, H.

CLINICAL STUDY: CARDIAC ELECTROPHYSIOLOGY

Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease

Vincent Probst, MD^*, Florence Kyndt, PharmD, PhD, Franck Potet, MBs, Jean-Noel Trochu, MD^*, Guy Mialet, MD, Sophie Demolombe, PhD, Jean-Jacques Schott, PhD, Isabelle Baró, PhD, Denis Escande, MD, PhD^,* and Hervé Le Marec, MD, PhD^*

^* Cardiology Department, Hôpital G&R Laennec, Nantes, France
Institut National de la Santé et de la Recherche Médicale (INSERM) U533, Faculté de Médecine, Nantes, France
Centre Hospitalier de La Roche/Yon, France

Manuscript received June 4, 2002; revised manuscript received August 29, 2002, accepted September 20, 2002.

^* Reprint requests and correspondence: Dr. Denis Escande, INSERM U533, 1 rue Gaston Veil, Faculté de Médecine, 44035 Nantes, France.
denis.escande{at}nantes.inserm.fr

OBJECTIVES: The goal of this study was to investigate the genotype-to-phenotype relationship between SCN5A gene mutation and progressive cardiac conduction defect in order to gain insights into the pathophysiologic mechanisms of the disease.

BACKGROUND: Progressive cardiac conduction defect is a frequent disease commonly attributed to degeneration and fibrosis of the His bundle and its branches. In a French family, we have identified a splicing mutation in the SCN5A gene leading to hereditary progressive cardiac conduction defect.

METHODS: We have extended the size of the pedigree and phenotyped and genotyped all family members, and also investigated in vitro the functional consequences of the mutation.

RESULTS: Among 65 potentially affected members, 25 individuals were carriers of the IVS.22+2 TC SCN5A mutation. In relation to aging, gene carriers exhibit various types of conduction defects. P-wave, PR, and QRS duration increased progressively with age in gene carriers and in noncarriers. Whatever the age, conduction parameters were longer in gene carriers. The widening in the QRS complex with aging was more pronounced in gene carriers older than 40 years. Functional studies show that the IVS.22+2 TC SCN5A mutation lead to exon 22 skipping and to a complete loss of function of the affected allele, but to a normal trafficking of the mutated gene product.

CONCLUSIONS: Our findings demonstrate that hereditary Lenègre disease is caused by a haploinsufficiency mechanism, which in combination with aging leads to progressive alteration in conduction velocity.

Abbreviations and Acronyms   AV   atrioventricular   ECG   electrocardiogram   LAHB   left anterior hemiblock   LBBB   left bundle branch block   LPHB   left posterior hemiblock   PCR   polymerase chain reaction   RBBB   right bundle branch block   WT   wild-type

This article has been cited by other articles:

				M. J. Ackerman, S. G. Priori, S. Willems, C. Berul, R. Brugada, H. Calkins, A. J. Camm, P. T. Ellinor, M. Gollob, R. Hamilton, et al. HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) Europace, August 1, 2011; 13(8): 1077 - 1109. [Full Text] [PDF]

				X. Hao, Y. Zhang, X. Zhang, M. Nirmalan, L. Davies, D. Konstantinou, F. Yin, H. Dobrzynski, X. Wang, A. Grace, et al. TGF-{beta}1-Mediated Fibrosis and Ion Channel Remodeling Are Key Mechanisms in Producing the Sinus Node Dysfunction Associated With SCN5A Deficiency and Aging Circ Arrhythm Electrophysiol, June 1, 2011; 4(3): 397 - 406. [Abstract] [Full Text] [PDF]

				D. Kattygnarath, S. Maugenre, N. Neyroud, E. Balse, C. Ichai, I. Denjoy, G. Dilanian, R. P. Martins, V. Fressart, M. Berthet, et al. MOG1: A New Susceptibility Gene for Brugada Syndrome Circ Cardiovasc Genet, June 1, 2011; 4(3): 261 - 268. [Abstract] [Full Text] [PDF]

				A. A. M. Wilde and R. Brugada Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel Circ. Res., April 1, 2011; 108(7): 884 - 897. [Abstract] [Full Text] [PDF]

				D. S. Park and G. I. Fishman The Cardiac Conduction System Circulation, March 1, 2011; 123(8): 904 - 915. [Full Text] [PDF]

				V. Probst, A. A.M. Wilde, J. Barc, F. Sacher, D. Babuty, P. Mabo, J. Mansourati, S. Le Scouarnec, F. Kyndt, C. Le Caignec, et al. SCN5A Mutations and the Role of Genetic Background in the Pathophysiology of Brugada Syndrome Circ Cardiovasc Genet, December 1, 2009; 2(6): 552 - 557. [Abstract] [Full Text] [PDF]

				C. A. Remme, B. P. Scicluna, A. O. Verkerk, A. S. Amin, S. van Brunschot, L. Beekman, V. H.M. Deneer, C. Chevalier, F. Oyama, H. Miyazaki, et al. Genetically Determined Differences in Sodium Current Characteristics Modulate Conduction Disease Severity in Mice With Cardiac Sodium Channelopathy Circ. Res., June 5, 2009; 104(11): 1283 - 1292. [Abstract] [Full Text] [PDF]

				I. Six, J.-S. Hermida, H. Huang, L. Gouas, V. Fressart, N. Benammar, B. Hainque, I. Denjoy, M. Chahine, and P. Guicheney 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, January 1, 2008; 10(1): 79 - 85. [Abstract] [Full Text] [PDF]

				H. V.M. van Rijen and J. M.T. de Bakker Penetrance of monogenetic cardiac conduction diseases. A matter of conduction reserve? Cardiovasc Res, December 1, 2007; 76(3): 379 - 380. [Full Text] [PDF]

				J. Guo, S. Zhan, J. Somers, R. E. Westenbroek, W. A. Catterall, D. E. Roach, R. S. Sheldon, J. P. Lees-Miller, P. Li, Y. Shimoni, et al. Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2669 - H2679. [Abstract] [Full Text] [PDF]

				D.-M. Niu, B. Hwang, H.-W. Hwang, N. H Wang, J.-Y. Wu, P.-C. Lee, J.-C. Chien, R.-C. Shieh, and Y.-T. Chen A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect J. Med. Genet., October 1, 2006; 43(10): 817 - 821. [Abstract] [Full Text] [PDF]

				J. A. Camacho, S. Hensellek, J.-S. Rougier, S. Blechschmidt, H. Abriel, K. Benndorf, and T. Zimmer Modulation of Nav1.5 Channel Function by an Alternatively Spliced Sequence in the DII/DIII Linker Region J. Biol. Chem., April 7, 2006; 281(14): 9498 - 9506. [Abstract] [Full Text] [PDF]

				K. Liu, T. Yang, P. C. Viswanathan, and D. M. Roden New Mechanism Contributing to Drug-Induced Arrhythmia: Rescue of a Misprocessed LQT3 Mutant Circulation, November 22, 2005; 112(21): 3239 - 3246. [Abstract] [Full Text] [PDF]

				T. A.B. van Veen, M. Stein, A. Royer, K. Le Quang, F. Charpentier, W. H. Colledge, C. L.-H. Huang, R. Wilders, A. A. Grace, D. Escande, et al. Impaired Impulse Propagation in Scn5a-Knockout Mice: Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging Circulation, September 27, 2005; 112(13): 1927 - 1935. [Abstract] [Full Text] [PDF]

				M. Lei, C. Goddard, J. Liu, A.-L. Leoni, A. Royer, S. S.-M. Fung, G. Xiao, A. Ma, H. Zhang, F. Charpentier, et al. Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a J. Physiol., September 1, 2005; 567(2): 387 - 400. [Abstract] [Full Text] [PDF]

				S. Demolombe, C. Marionneau, S. Le Bouter, F. Charpentier, and D. Escande Functional genomics of cardiac ion channel genes Cardiovasc Res, August 15, 2005; 67(3): 438 - 447. [Abstract] [Full Text] [PDF]

				G. C.M. Beaufort-Krol, M. P. van den Berg, A. A.M. Wilde, J. P. van Tintelen, J. W. Viersma, C. R. Bezzina, and M. Th.E. Bink-Boelkens Developmental Aspects of Long QT Syndrome Type 3 and Brugada Syndrome on the Basis of a Single SCN5A Mutation in Childhood J. Am. Coll. Cardiol., July 19, 2005; 46(2): 331 - 337. [Abstract] [Full Text] [PDF]

				A. Royer, T. A.B. van Veen, S. Le Bouter, C. Marionneau, V. Griol-Charhbili, A.-L. Leoni, M. Steenman, H. V.M. van Rijen, S. Demolombe, C. A. Goddard, et al. Mouse Model of SCN5A-Linked Hereditary Lenegre's Disease: Age-Related Conduction Slowing and Myocardial Fibrosis Circulation, April 12, 2005; 111(14): 1738 - 1746. [Abstract] [Full Text] [PDF]

				H. V.M. van Rijen, J. M.T. de Bakker, and T. A.B. van Veen Hypoxia, electrical uncoupling, and conduction slowing: Role of conduction reserve Cardiovasc Res, April 1, 2005; 66(1): 9 - 11. [Full Text] [PDF]

				J. P.P. Smits, M. W. Veldkamp, and A. A.M. Wilde Mechanisms of inherited cardiac conduction disease Europace, January 1, 2005; 7(2): 122 - 137. [Abstract] [Full Text] [PDF]

				C. Tveskov, A. Skytthe, P. Arnsbo, J. W. Vaupel, M. Møller, and K. Christensen Twins with implanted pacemakers: Is there an increased mortality risk for the co-twin? A follow-up study based on the Danish Twin Registry and the Danish Pacemaker Register Europace, January 1, 2005; 7(6): 598 - 603. [Abstract] [Full Text] [PDF]

				D. P. Zipes The year in electrophysiology J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1306 - 1314. [Full Text] [PDF]