Referenced in: none

Automatically associated channels: Kv11.1 , Nav1.5

Title: Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome.

Authors: Arie O Verkerk, Ronald Wilders, Eric Schulze-Bahr, Leander Beekman, Zahurul A Bhuiyan, Jessica Bertrand, Lars Eckardt, Dongxin Lin, Martin Borggrefe, Günter Breithardt, Marcel M A M Mannens, Hanno L Tan, Arthur A M Wilde, Connie R Bezzina

Journal, date & volume: Cardiovasc. Res., 2005 Dec 1 , 68, 441-53

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16043162

Abstract
Brugada syndrome (BrS) is an inherited electrical disorder associated with a high incidence of sudden death. In a minority of patients, it has been linked to mutations in SCN5A, the gene encoding the pore-forming alpha-subunit of the cardiac Na(+) channel. Other causally related genes still await identification. We evaluated the role of HERG (KCNH2), which encodes the alpha-subunit of the rapid delayed rectifier K(+) channel (I(Kr)), in BrS.In two unrelated SCN5A mutation-negative patients, different amino acid changes in the C-terminal domain of the HERG channel (G873S and N985S) were identified. Voltage-clamp experiments on transfected HEK-293 cells show that these changes increase I(Kr) density and cause a negative shift of voltage-dependent inactivation, resulting in increased rectification. Action potential (AP) clamp experiments reveal increased transient HERG peak currents (I(peak)) during phase-0 and phase-1 of the ventricular AP, particularly at short cycle length. Computer simulations demonstrate that the increased I(peak) enhances the susceptibility to loss of the AP-dome typically in right ventricular subepicardial myocytes, thereby contributing to the BrS phenotype.Our study reveals a modulatory role of I(Kr) in BrS. These findings may provide better understanding of BrS and have implications for diagnosis and therapy.