(Gene: KCNE2; potassium voltage-gated channel, Isk-related family, member 2)
The KCNE2 gene was first cloned by Abbott et al. (1999) and encodes a MinK- (LQT5-) related peptide-1 (MiRP1) that is a small integral membrane subunit to assemble with the HERG (LQT2) gene product to form the I(Kr) channel. When studied expression of MiRP1 and HERG in CHO cells, the complexes required a depolarization at more positive voltages to achieve half-maximum activation and lead to a faster deactivation of I(Kr) channels. MiRP1 is a 123-amino acid protein containing consensus sequences for two N-linked glycosylation sites (N6 and N29) and two protein kinase C-mediated phosphorylation sites (T71 and S74). Northern blot analysis detected MiRP1 expression in the human heart and muscle.
Abbott et al. (1999) showed that complexes by the MiRP1 and HERG proteins resemble the native cardiac I(Kr) channels in important properties (gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031). To assess the potential role of MiRP1 in LQT syndrome, Abbott et al. (1999) screened 20 patients with drug-induced arrhythmias and 230 with inherited or sporadic LQT syndrome for mutations in KCNE2. Three missense mutations associated with LQT syndrome were identified; these were absent in 1,010 unrelated healthy individuals serving as controls. I(Kr) channels formed with mutant MiRP1 subunits and HERG showed slower activation, faster deactivation, and increased drug sensitivity. One missense mutation, Q9E, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic, and, thus, suggests a mechanism for acquired arrhythmias: a genetically based reduction in potassium currents remains clinically silent until combined with additional stressors. These findings support a theory for genetic factors in arrhythmogenesis that invokes superimposition of genetic and environmental factors to diminish progressively the capacity of cardiac ion channels to terminate the action potential in normal fashion.
Overall, KCNE2 mutations among LQTS patients are rare and LQT6 has the genetic variant with the lowest prevalence (0.5-1%).