© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family
aSino-German Laboratory for Molecular Medicine and Center for Molecular Cardiology, Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, 167 Beilishilu, Beijing 100037, China
bThe Centre for Molecular Neurobiology Hamburg, The University of Hamburg, Martinistrasse 52, Hamburg 20246, Germany
huirutai{at}sglab.org
* Corresponding author. Sino-German Laboratory, Center for Molecular Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, 167 Beilishilu, Beijing 100037, China. Tel.: +86-10-6833-3902; fax: +86-10-6833-1730.
Objectives: To identify the underlying genetic basis of a Chinese pedigree with Long QT syndrome, the causally related genes were screened in a family and the functional consequence of the identified gene mutation was evaluated in vitro. Methods: Mutations in the five defined Long QT syndrome related genes were screened with polymerase chain reaction and single-strand conformation polymorphism methods and direct sequencing. The electrophysiological properties of the identified mutation were characterized in the Xenopus oocyte heterologous expression system. Results: A novel missense mutation, G to A at position 154 in the KCNE1 gene was identified in a Chinese Long QT syndrome family, which leads to an amino acid substitution of arginine (R) for glycine (G) at position 52 (G52R-KCNE1). Of 26 family members (one DNA was not available), seven were mutation carriers and two of them with normal electrocardiogram. Compared with wild-type KCNE1/KCNQ1 channels, coexpression of G52R-KCNE1 with KCNQ1 in Xenopus oocytes did not amplify the KCNQ1 current amplitudes and slightly changed the activation kinetics of the KCNQ1 channels. Coexpression of KCNQ1 together with wild type KCNE1 and G52R-KCNE1 reduced the wild-type Iks current amplitude by 50%, whereas other biophysical properties of the Iks were not altered. Conclusions: Our findings indicate that glycine52 in the transmembrane domain is critical for KCNE1 function. The mutant G52R-KCNE1 has a dominant negative effect on Iks current, which reduces the Iks current amplitude and leads to a prolongation of the cardiac action potential. This could underlie the molecular mechanism of ventricular arrhythmias and sudden death in those patients.
KEYWORDS K-channel; Arrhythmias; Long QT syndrome