Novel KCNE3 mutation reduces repolarizing potassium current and associated with long QT syndrome

✍ Scribed by Seiko Ohno; Futoshi Toyoda; Dimitar P Zankov; Hidetada Yoshida; Takeru Makiyama; Keiko Tsuji; Toshihiro Honda; Kazuhiko Obayashi; Hisao Ueyama; Wataru Shimizu; Yoshihiro Miyamoto; Shiro Kamakura; Hiroshi Matsuura; Toru Kita; Minoru Horie

• Book ID: 102262881
• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 279 KB
• Volume: 30
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20834

✦ Synopsis

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.R99kH 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-yearold 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) 1KCNE3(E3)-R99kH channel significantly reduced outward current compared to Q11E3-WT, though the current density of the Q11E3-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.