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Cardiovascular Research 2005 68(3):441-453; doi:10.1016/j.cardiores.2005.06.027
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Copyright © 2005, European Society of Cardiology

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

Arie O. Verkerka,b,*, Ronald Wildersb, Eric Schulze-Bahrc,d, Leander Beekmana, Zahurul A. Bhuiyana,e, Jessica Bertrandc, Lars Eckardtd, Dongxin Linf, Martin Borggrefeg, Günter Breithardtc,d, Marcel M.A.M. Mannense, Hanno L. Tana, Arthur A.M. Wildea and Connie R. Bezzinaa,e

aDepartment of Experimental Cardiology, Academic Medical Center, University of Amsterdam, The Netherlands
bDepartment of Physiology, Academic Medical Center, University of Amsterdam, The Netherlands
cMolecular Cardiology, Institute for Arteriosclerosis Research, University of Münster, Germany
dDepartment of Cardiology and Angiology, University Hospital of Münster, Germany
eDepartment of Clinical Genetics, Academic Medical Center, University of Amsterdam, The Netherlands
fDepartment of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, PR China
gDepartment of Cardiology, University Hospital Mannheim, Germany

* Corresponding author. Department of Physiology, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 20 5664670; fax: +31 20 6919319. Email address: A.O.Verkerk{at}amc.uva.nl

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 (IKr), 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 IKr 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 (Ipeak) during phase-0 and phase-1 of the ventricular AP, particularly at short cycle length. Computer simulations demonstrate that the increased Ipeak 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 IKr in BrS. These findings may provide better understanding of BrS and have implications for diagnosis and therapy.

KEYWORDS Arrhythmia; Sudden death; Ion channels; K-channel; Genetics

Time for primary review 24 days


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