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.


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.


CONCLUSIONS
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.
Verkerk
Arie O
AO
Department of Experimental Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. A.O.Verkerk@amc.uva.nl
Wilders
Ronald
R
Schulze-Bahr
Eric
E
Beekman
Leander
L
Bhuiyan
Zahurul A
ZA
Bertrand
Jessica
J
Eckardt
Lars
L
Lin
Dongxin
D
Borggrefe
Martin
M
Breithardt
Günter
G
Mannens
Marcel M A M
MM
Tan
Hanno L
HL
Wilde
Arthur A M
AA
Bezzina
Connie R
CR
D000200:Action Potentials / Q000235:genetics; D000704:Analysis of Variance; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014162:Transfection / Q000379:methods
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human