KCNQ1 gain-of-function mutation in familial atrial fibrillation.
Atrial fibrillation (AF) is a common cardiac arrhythmia whose molecular etiology is poorly understood. We studied a family with hereditary persistent AF and identified the causative mutation (S140G) in the KCNQ1 (KvLQT1) gene on chromosome 11p15.5. The KCNQ1 gene encodes the pore-forming alpha subunit of the cardiac I(Ks) channel (KCNQ1/KCNE1), the KCNQ1/KCNE2 and the KCNQ1/KCNE3 potassium channels. Functional analysis of the S140G mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and the KCNQ1/KCNE2 currents, which contrasts with the dominant negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Thus, the S140G mutation is likely to initiate and maintain AF by reducing action potential duration and effective refractory period in atrial myocytes.
Chen
Yi-Han
YH
Department of Cardiology, Tongji Hospital, and Institute of Medical Genetics, Tongji University, 399 Xin Cun Road, Shanghai 200065, People's Republic of China. drchen@public7.sta.net.cn
Xu
Shi-Jie
SJ
Bendahhou
Said
S
Wang
Xiao-Liang
XL
Wang
Ying
Y
Xu
Wen-Yuan
WY
Jin
Hong-Wei
HW
Sun
Hao
H
Su
Xiao-Yan
XY
Zhuang
Qi-Nan
QN
Yang
Yi-Qing
YQ
Li
Yue-Bin
YB
Liu
Yi
Y
Xu
Hong-Ju
HJ
Li
Xiao-Fei
XF
Ma
Ning
N
Mou
Chun-Ping
CP
Chen
Zhu
Z
Barhanin
Jacques
J
Huang
Wei
W
D000200:Action Potentials; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000503:physiopathology; D019556:COS Cells; D002648:Child; D002681:China; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004562:Electrocardiography; D005260:Female; D006239:Haplotypes; D006325:Heart Atria / Q000503:physiopathology; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008126:Lod Score; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated
C418492:KCNE3 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk)