NovelKCNE3mutation reduces repolarizing potassium current and associated with long QT syndrome
| Autor: | Toru Kita, Keiko Tsuji, Takeru Makiyama, Hidetada Yoshida, Kazuhiko Obayashi, Hiroshi Matsuura, Shiro Kamakura, Wataru Shimizu, Futoshi Toyoda, Toshihiro Honda, Minoru Horie, Hisao Ueyama, Yoshihiro Miyamoto, Dimitar P. Zankov, Seiko Ohno |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Proband congenital hereditary and neonatal diseases and abnormalities Patch-Clamp Techniques Adolescent Long QT syndrome Mutation Missense Single-nucleotide polymorphism Torsades de pointes CHO Cells Biology Transfection medicine.disease_cause Membrane Potentials Cricetulus Cricetinae Chlorocebus aethiops Genetics medicine Animals Humans Missense mutation Amino Acid Sequence Genetics (clinical) Aged Mutation Base Sequence KCNE2 KCNE3 medicine.disease Long QT Syndrome Potassium Channels Voltage-Gated COS Cells KCNQ1 Potassium Channel biology.protein Female Protein Binding |
| Zdroj: | Human Mutation. 30:557-563 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.20834 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text