Human KCNQ1 S140G mutation is associated with atrioventricular blocks.
BACKGROUND
We recently reported that an S140G mutation in human KCNQ1, an alpha subunit of potassium channels, was involved in the pathogenesis of familial atrial fibrillation (AF), but it is not clear whether the mutation is associated with other cardiac arrhythmias.


OBJECTIVE
The purpose of this study was to further explore the association of the KCNQ1 S140G mutation with cardiac arrhythmias.


METHODS
We produced a transgenic mouse model with myocardium-specific expression of the human KCNQ1 S140G mutation under the control of an alpha-cardiac myosin heavy chain promoter by standard transgenic procedure and evaluated the relationship between the KCNQ1 mutation and its phenotypes in a human family.


RESULTS
Four lines of transgenic mice were established with a high level of human KCNQ1 S140G expression in the heart. Frequent episodes of first-, second-, advanced-, or third-degree atrioventricular block (AVB) occurred in at least 65% of transgenic descendants from the four lines. However, none of the five wild-type transgenic lines presented with AVBs. HMR1556, a KCNQ1-specific blocker, can terminate the AVBs. With the exception of at most three AF individuals, at least 13 AF patients were found to show obviously slow ventricular response, which may be one manifestation of AVBs. Interestingly, AF was not detected in these transgenic mice.


CONCLUSIONS
The results suggest that human KCNQ1 S140G is also likely to be a causative mutation responsible for AVBs. The transgenic mouse model is a potential tool to explore mechanisms of AVBs.
Yang
Yiqing
Y
Department of Cardiology, Tongji Hospital, Shanghai, China.
Liu
Yi
Y
Dong
Xiongjian
X
Kuang
Ying
Y
Lin
Jie
J
Su
Xiaoyan
X
Peng
Luying
L
Jin
Qingfeng
Q
He
Yusong
Y
Liu
Ban
B
Pan
Zhiwen
Z
Li
Li
L
Zhu
Qian
Q
Lin
Xiaoping
X
Zhou
Qinshu
Q
Pan
Qin
Q
Eurlings
Petra M H
PM
Fei
Jian
J
Wang
Zhugang
Z
Chen
Yi Han
YH
D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000503:physiopathology; D001283:Atrioventricular Node / Q000187:drug effects / Q000503:physiopathology; D002681:China; D002839:Chromans / Q000494:pharmacology; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D005998:Glycine; D006327:Heart Block / Q000235:genetics* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006352:Heart Ventricles / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D051657:KCNQ1 Potassium Channel / Q000187:drug effects / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012107:Research Design; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000494:pharmacology
D002839:Chromans; C420023:HMR 1556; D051657:KCNQ1 Potassium Channel; D013449:Sulfonamides; D012694:Serine; D005998:Glycine