Long QT syndrome
As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited long QT syndrome, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced long QT syndrome. In several cases, specific KCNE2 sequence variants increase the susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated. Long QT syndrome predisposes to potentially lethal ventricular cardiac arrhythmias including torsades de pointe, which can degenerate into ventricular fibrillation and sudden cardiac death. Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis. KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations.