Characterization of a Chinese KCNQ1 mutation (R259H) that shortens repolarization and causes short QT syndrome 2.
OBJECTIVE
To evaluate the association between a KCNQ1 mutation, R259H, and short QT syndrome (SQTS) and to explore the electrophysiological mechanisms underlying their association.


METHODS
We performed genetic screening of SQTS genes in 25 probands and their family members (63 patients). We used direct sequencing to screen the exons and intron-exon boundaries of candidate genes that encode ion channels which contribute to the repolarization of the ventricular action potential, including KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, CACNA1c, CACNB2b and CACNA2D1. In one of the 25 SQTS probands screened, we discovered a KCNQ1 mutation, R259H. We cloned R259H and transiently expressed it in HEK-293 cells; then, currents were recorded using whole cell patch clamp techniques.


RESULTS
R259H-KCNQ1 showed significantly increased current density, which was approximately 3-fold larger than that of wild type (WT) after a depolarizing pulse at 1 s. The steady state voltage dependence of the activation and inactivation did not show significant differences between the WT and R259H mutation (P > 0.05), whereas the time constant of deactivation was markedly prolonged in the mutant compared with the WT in terms of the test potentials, which indicated that the deactivation of R259H was markedly slower than that of the WT. These results suggested that the R259H mutation can effectively increase the slowly activated delayed rectifier potassium current (I Ks) in phase 3 of the cardiac action potential, which may be an infrequent cause of QT interval shortening.


CONCLUSIONS
R259H is a gain-of-function mutation of the KCNQ1 channel that is responsible for SQTS2. This is the first time that the R259H mutation was detected in Chinese people.
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Zhi-Juan
ZJ
Wu
Department of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yun
Y
Huang
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Yi-Cheng
YC
Fu
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Xiao-Jing
XJ
Zhao
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Chao
C
Zhu
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Yu
Y
Zhang
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Bin
B
Xu
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Qing-Lei
QL
Zhu
Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
Yang
Y
Li
Ion channel; KCNQ1 gene; Mutation; Short QT syndrome; Slowly activated delayed rectifier potassium current