A Novel Missense Mutation, I890T, in the Pore Region of Cardiac Sodium Channel Causes Brugada Syndrome

Tarradas, Anna; Selga, Elisabet; Beltran-Alvarez, Pedro; Pérez-Serra, Alexandra; Riuró, Helena; Picó, Ferran; Iglesias, Anna; Campuzano, Oscar; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Pérez, Guillermo J.; Scornik, Fabiana S.; Brugada, Ramon

Abstract

Brugada syndrome (BrS) is a life-threatening, inherited arrhythmogenic syndrome associated with autosomal dominant mutations in SCN5A, the gene encoding the cardiac Na+ channel alpha subunit (Nav1.5). The aim of this work was to characterize the functional alterations caused by a novel SCN5A mutation, I890T, and thus establish whether this mutation is associated with BrS. The mutation was identified by direct sequencing of SCN5A from the proband's DNA. Wild-type (WT) or I890T Nav1.5 channels were heterologously expressed in human embryonic kidney cells. Sodium currents were studied using standard whole cell patch-clamp protocols and immunodetection experiments were performed using an antibody against human Nav1.5 channel. A marked decrease in current density was observed in cells expressing the I890T channel (from -52.0±6.5 pA/pF, n = 15 to -35.9±3.4 pA/pF, n = 22, at -20 mV, WT and I890T, respectively). Moreover, a positive shift of the activation curve was identified (V1/2 = -32.0±0.3 mV, n = 18, and -27.3±0.3 mV, n = 22, WT and I890T, respectively). No changes between WT and I890T currents were observed in steady-state inactivation, time course of inactivation, slow inactivation or recovery from inactivation parameters. Cell surface protein biotinylation analyses confirmed that Nav1.5 channel membrane expression levels were similar in WT and I890T cells. In summary, our data reveal that the I890T mutation, located within the pore of Nav1.5, causes an evident loss-of-function of the channel. Thus, the BrS phenotype observed in the proband is most likely due to this mutation. © 2013 Tarradas et al.

Citation

Tarradas, A., Selga, E., Beltran-Alvarez, P., Pérez-Serra, A., Riuró, H., Picó, F., …Brugada, R. (2013). A Novel Missense Mutation, I890T, in the Pore Region of Cardiac Sodium Channel Causes Brugada Syndrome. PLoS ONE, 8(1), Article e53220. https://doi.org/10.1371/journal.pone.0053220

• Journal Article Type: Article
• Acceptance Date: Nov 27, 2012
• Online Publication Date: Jan 7, 2013
• Publication Date: Jan 7, 2013
• Deposit Date: Apr 1, 2022
• Publicly Available Date: Apr 12, 2022
• Journal: PLoS ONE
• Print ISSN: 1932-6203
• Electronic ISSN: 1932-6203
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 1
• Article Number: e53220
• DOI: https://doi.org/10.1371/journal.pone.0053220
• Public URL: https://hull-repository.worktribe.com/output/3570098