Effects of mutations in KCNQ1 and KCNE1 on trafficking and channel function

LQTS (long QT syndrome) is an important cause of cardiac sudden death. LQTS is characterized by a prolongation of the QT interval on an electrocardiogram. This prolongation predisposes the individual to torsade-de-pointes and subsequent sudden death by ventricular fibrillation. Mutations in a number of genes that encode ion channels have been implicated in LQTS. Hereditary mutations in the αand β-subunits, KCNQ1 and KCNE1 respectively, of the K+ channel pore IKs are the commonest cause of LQTS and account for LQTS types 1 and 5 respectively (LQT1 and LQT5). Recently, it has been shown that disease pathogenesis in LQT1 can be influenced by the abnormal trafficking of KCNQ1. In comparison, whether defective trafficking of KCNE1 plays a role in LQT5 is less well established. LQTS (long QT syndrome) types 1 and 5 LQTS causes sudden death, syncope and seizures in affected individuals. LQT1 and LQT5 are associated with mutations in the KVLQT1 and KCNE1 genes respectively [1–3]. The products of the KVLQT1 and KCNE1 genes, KCNQ1 and KCNE1, form the αand β-subunits of the potassium channel complex that produces the repolarizing IKs current in cardiac myocytes [4,5]. The IKs channel complex consists of four KCNQ1 α-subunits and probably two KCNE1 β-subunits [6] (Figure 1). KCNQ1, when expressed without KCNE1, is opened by progressive membrane depolarizations and gives rise to a slowly activating and deactivating potassium current. During longer depolarization steps, a proportion of the channels are inactivated [3]. In the presence of KCNE1, the currents produced are much larger and have very slow activation characteristics. There is also a positive shift in the voltage activation threshold and, in comparison with KCNQ1 alone, a reduced level of inactivation [3]. Mutations in KCNQ1 and KCNE1 account for two clinical syndromes, the RWS (Romano–Ward syndrome) and the rarer JLNS (Jervell–Lange-Nielsen syndrome). RWS is inherited in an autosomal dominant fashion and JLNS is inherited in an autosomal recessive fashion. Individuals with JLNS also suffer from profound hearing loss that is not found in individuals with RWS [7,8]. Traditionally, in LQT1, it was assumed that the mutant channels were incorrectly functioning complexes present at the membrane surface [9]. Recently, various KCNQ1 mutants have been shown to be trafficked abnormally [10,11]. Whether defective trafficking of KCNE1 can influence disease pathogenesis in LQT5 is less well established, but several pieces of evidence suggest that this mechanism may play a role.