The sodium channel gene SCN5A and potassium channel genes KCNQ1 and KCNH2 have been widely reported to be genetic risk factors for arrhythmia including Brugada syndrome and long QT syndrome (LQTS).
The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I Kr, the current encoded by HERG.
The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias.
Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed.
To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP.
Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K(+) currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations).
Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug.
QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG).
In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias.
Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na(+) channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism.
In this study, we analyzed the genetic variants of KCNQ1, KCNH2, and SCN5A in patients from seven cohorts (total N = 11945, including patients clinically suspected to have inherited arrhythmia [n = 122], other cardiovascular diseases [n = 1045], epilepsy [n = 4797], or other diseases [n = 5841], and healthy controls [n = 140]) who had undergone genetic testing.
Genetic mutations in KCNH2, which encodes hERG, the alpha subunit of the potassium channel responsible for the I<sub>Kr</sub> current, cause long QT syndrome (LQTS), an inherited cardiac arrhythmia disorder.
Our findings provide insight into the pathogenesis of homozygous kcnh2 mutations and expand the use of zebrafish mutants as a model system to study human arrhythmias.
Mutations in the human ether-a-go-go-related gene (HERG) cause long QT syndrome, an inherited disorder of cardiac repolarization that predisposes affected individuals to life-threatening arrhythmias.
The NTRs were also predicted to form from truncation mutations that were linked to type 2 long QT syndrome (LQTS), a cardiac arrhythmia disorder associated with mutations in the hERG gene.
Mutations in the human ether-a-go-go-related gene (HERG, KCNH2) cause the chromosome 7-linked LQT2 form of congenital LQTS, which is characterized by a prolonged QT interval and a bifid T-wave with an increased susceptibility to life-threatening cardiac arrhythmias, especially in children.
Reduced activity of Kv11.1 channels causes long QT syndrome type 2, a disorder that increases the risk of cardiac arrhythmias and sudden cardiac arrest.