title: Novel KCNE3 mutation reduces repolarizing potassium current and associated with long QT syndrome.
abstract: Long QT syndrome (LQTS) is an inherited disease involving mutations in the genes encoding a number of cardiac ion channels and a membrane adaptor protein. Among the genes that are responsible for LQTS, KCNE1 and KCNE2 are members of the KCNE family of genes, and function as ancillary subunits of Kv channels. The third KCNE gene, KCNE3, is expressed in cardiac myocytes and interacts with KCNQ1 to change the channel properties. However, KCNE3 has never been linked to LQTS. To investigate the association between KCNE3 and LQTS, we conducted a genetic screening of KCNE3 mutations and single nucleotide polymorphisms (SNPs) in 485 Japanese LQTS probands using DHPLC-WAVE system and direct sequencing. Consequently, we identified two KCNE3 missense mutations, located in the N- and C-terminal domains. The functional effects of these mutations were examined by heterologous expression systems using CHO cells stably expressing KCNQ1. One mutation, p.R99lambdaH was identified in a 76-year-old woman who suffered torsades de pointes (TdP) after administration of disopyramide. Another mutation, p.T4A was identified in a 16-year-old boy and 67-year-old woman. Although the boy carried another KCNH2 mutation, he was asymptomatic. On the other hand, the woman suffered from hypokalemia-induced TdP. In a series of electrophysiological analyses, the KCNQ1(Q1)+KCNE3(E3)-R99lambdaH channel significantly reduced outward current compared to Q1+E3-WT, though the current density of the Q1+E3-T4A channel displayed no statistical significance. This is the first report of KCNE3 mutations associated with LQTS. Screening for variants in the KCNE3 gene is of clinical importance for LQTS patients.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Dimitar P
authors.initials: DP
authors.lastname: Zankov
authors.forename: Hidetada
authors.initials: H
authors.lastname: Yoshida
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Tsuji
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Honda
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Obayashi
authors.forename: Hisao
authors.initials: H
authors.lastname: Ueyama
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D014162:Transfection
chemical_list: C418492:KCNE3 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated