Loss of function associated with novel mutations of the SCN5A gene in patients with Brugada syndrome.

Publication Type:

Journal Article


Can J Cardiol, Volume 20, Issue 4, p.425-30 (2004)


Adult, Bundle-Branch Block, Codon, Nonsense, Defibrillators, Implantable, Echocardiography, Electric Countershock, Electrocardiography, Female, Genetic Markers, Genetic Predisposition to Disease, Heart Conduction System, Humans, Male, Microscopy, Confocal, Middle Aged, Mutation, Missense, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Phenotype, Sodium Channels, Statistics as Topic, Syndrome, Ventricular Fibrillation


<p><b>BACKGROUND: </b>Ventricular fibrillation is one of the leading causes of death in North America. Brugada syndrome is characterized by ST segment elevation on the right precordial leads V1 through V3 and right bundle branch block, and may cause sudden death. Mutations in the SCN5A gene encoding the cardiac voltage-gated Na+ channel (hNav1.5) are associated with Brugada syndrome.</p><p><b>OBJECTIVES: </b>In this study, three novel mutations on the SCN5A gene were identified and characterized in different patients with Brugada syndrome.</p><p><b>METHODS: </b>Blood samples were collected from patients with Brugada syndrome for gene screening. Mutations found on the SCN5A gene in these patients were reproduced in vitro on hNav1.5 background. Wild type and mutant channels expressed in tsA201 cells were characterized using the patch clamp technique in whole cell configuration and/or confocal microscopy.</p><p><b>RESULTS: </b>No current could be recorded from cells expressing the hNav1.5/G1740R mutant, incubated at 37 degrees C. However, at a lower incubation temperature (22 degrees C), macroscopic Na+ currents were recorded. Confocal microscopy study confirmed that at 37 degrees C, hNav1.5/G1740R mutant channels were retained in the endoplasmic reticulum. The E473X and N1774+12X mutants produced truncated proteins and did not express any currents; however, coexpression of each of these mutants with wild type channels shows 50% reduction of Na+ currents.</p><p><b>CONCLUSION: </b>This study confirms that the loss of function of cardiac Na+ channels is the basis of the Brugada syndrome clinical phenotype.</p>

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