Mutations in KCNE1 in long QT syndrome (LQTS): Insights into mechanism of LQTS and drug sensitivity?

Abstract

e d a C t y a K K t b t i c i i c r t i K t L r p r n c t i r c s t t t t l n t t o b In this issue of Heart Rhythm, Wu and colleagues decribe a mutation in KCNE1, the 129 amino acid single embrane-spanning peptide -subunit that associates with he voltage-gated KCNQ1 channel to form the slow delayed ectifier channel (IKs) in the heart, which causes the long QT yndrome type 5 (LQT5). This mutation, Y81C, is located n the post-transmembrane domain region of the KCNE1 minK) channel in close proximity to three other LQT5 utations (S74L, D76N, and W87R). Previously, Lai et al escribed this same mutation in a patient with compound eterozygous KCNE1 mutations (Y81C, K70N). In the reort by Wu et al, the authors examined the effects of the 81C mutation on the function and drug sensitivity of IKs hannels and provide an interesting experimental approach nd potentially novel insight into IKs structure-function corelations and future therapeutic options. KCNE1 interacts with the KCNQ1 channel subunit via ts transmembrane domain, which adopts an -helical strucure and interacts with the S6 helix in the pore domain of CNQ1. In addition, it is speculated that the cytoplasmic egion of KCNE1, a conserved region localized 20–25 mino acids distal to the transmembrane helix, also plays a ole in channel conductance and the function of the CNQ1/KCNE1 complex responsible for IKs. Typically, CNE1 increases KCNQ1 single-channel conductance, hich leads to an increase in the macroscopic current amlitude, shifts the voltage dependence of KCNQ1 channel ctivation in the positive direction, and slows its activation. s a result of this regulation, a slow buildup of IKs occurs nd results in repolarization abnormalities that translate into rolongation of the QT interval when loss-of-function muations occur or in pathologic shortening of the QT interval hen gain-of-function mutations occur. In the former, QTS (LQT1 when KCNQ1 is mutated, LQT5 when CNE1 is mutated) occurs, while the relatively newly escribed short QT syndrome or familial atrial fibrillation ccurs in the latter instance. Y81C is speculated to cause an QT5 phenotype, and the authors describe the detailed echanism that likely plays a role in generating this clinical henotype.