Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death.
BACKGROUND
A variety of mutations in HERG, the major subunit of the rapidly activating component of the cardiac delayed rectifier I(Kr), have been found to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to severe arrhythmogenic phenotypes leading to sudden cardiac death.


OBJECTIVE
We attempt to elucidate the mechanisms by which heterogeneous LQT2 genotypes can lead to prolongation of the action potential duration (APD) and consequently the QT interval on the ECG.


METHODS
We develop Markovian models of wild-type (WT) and mutant I(Kr) channels and incorporate these models into a comprehensive model of the cardiac ventricular cell.


RESULTS
Using this virtual transgenic cell model, we describe the effects of HERG mutations on the cardiac ventricular action potential (AP) and provide insight into the mechanism by which each defect results in a net loss of repolarizing current and prolongation of APD.


CONCLUSIONS
This study demonstrates which mutations can prolong APD sufficiently to generate early afterdepolarizations (EADs), which may trigger life-threatening arrhythmias. The severity of the phenotype is shown to depend on the specific kinetic changes and how they affect I(Kr) during the time course of the action potential. Clarifying how defects in HERG can lead to impaired cellular electrophysiology can improve our understanding of the link between channel structure and cellular function.
Clancy
C E
CE
Cardiac Bioelectricity Research and Training Center, Department of Physiology and Biophysics, 509 Wickenden Building, Case Western Reserve University, Cleveland, Ohio 44106-7207, USA.
Rudy
Y
Y
D000200:Action Potentials / Q000502:physiology; D027682:Cation Transport Proteins; D003198:Computer Simulation; D004268:DNA-Binding Proteins; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics*; D008390:Markov Chains; D008955:Models, Cardiovascular; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; 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