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

Background: 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. Methods and results: 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. Conclusion: 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. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved