Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics

Long-QT syndrome (LQTS) may cause syncope and sudden death due to cardiac tachyarrhythmia. Chromosome 7-linked LQTS (LQT2) has been correlated with mutations in the human ether-a-go-go-related gene (HERG). HERG forms voltage-gated K channels that may be associated with Mink-related peptide 1 (MiRP1), an auxiliary β-subunit. The channels mediate currents that resemble native I_Kr. Mutations in the KCNE2 gene encoding MiRP1 may also cause LQTS. In this study, the frequency of mutations in KCNE2 of 150 unrelated LQTS patients without known genotype and of 100 controls was analyzed using single-strand conformation polymorphism analysis and direct sequencing. We identified a novel missense mutation, V65 M, in the KCNE2 gene of a 17-year-old female with syncope and LQTS. Expression studies in Chinese hamster ovary cells revealed that mutant and wild-type MiRP1 co-localized with HERG subunits and formed functional channels. However, mutant HERG/MiRP1_V65M channels mediated currents with an accelerated inactivation time course compared with wild-type channels. The accelerated inactivation time course of HERG/MiRP1_V65M channels may decrease I_Kr current density of myocardial cells, thereby impairing the ability of myocytes to repolarize in response to sudden membrane depolarizations such as extrasystoles.