Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel.
BACKGROUND
The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go-related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I(Kr)). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder.


RESULTS
A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P<0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 (P<0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc.


CONCLUSIONS
Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.
Moss
Arthur J
AJ
Cardiology Unit of the Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA. heartajm@heart.rochester.edu
Zareba
Wojciech
W
Kaufman
Elizabeth S
ES
Gartman
Eric
E
Peterson
Derick R
DR
Benhorin
Jesaia
J
Towbin
Jeffrey A
JA
Keating
Mark T
MT
Priori
Silvia G
SG
Schwartz
Peter J
PJ
Vincent
G Michael
GM
Robinson
Jennifer L
JL
Andrews
Mark L
ML
Feng
Changyong
C
Hall
W Jackson
WJ
Medina
Aharon
A
Zhang
Li
L
Wang
Zhiqing
Z
D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D027682:Cation Transport Proteins; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D018450:Disease Progression; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D016017:Odds Ratio; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D011379:Prognosis; D016016:Proportional Hazards Models; D012042:Registries / Q000706:statistics & numerical data; D012044:Regression Analysis; D018570:Risk Assessment / Q000706:statistics & numerical data; D016019:Survival Analysis; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG
D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG