A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia.
KChIP2, a gene encoding three auxiliary subunits of Kv4.2 and Kv4.3, is preferentially expressed in the adult heart, and its expression is downregulated in cardiac hypertrophy. Mice deficient for KChIP2 exhibit normal cardiac structure and function but display a prolonged elevation in the ST segment on the electrocardiogram. The KChIP2(-/-) mice are highly susceptible to the induction of cardiac arrhythmias. Single-cell analysis revealed a substrate for arrhythmogenesis, including a complete absence of transient outward potassium current, I(to), and a marked increase in action potential duration. These studies demonstrate that a defect in KChIP2 is sufficient to confer a marked genetic susceptibility to arrhythmias, establishing a novel genetic pathway for ventricular tachycardia via a loss of the transmural gradient of I(to).
Kuo
H C
HC
Institute of Molecular Medicine, UCSD-Salk Program in Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cheng
C F
CF
Clark
R B
RB
Lin
J J
JJ
Lin
J L
JL
Hoshijima
M
M
Nguyêñ-Trân
V T
VT
Gu
Y
Y
Ikeda
Y
Y
Chu
P H
PH
Ross
J
J
Giles
W R
WR
Chien
K R
KR
D000200:Action Potentials / Q000502:physiology; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004562:Electrocardiography; D004622:Embryo, Mammalian / Q000378:metabolism; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006801:Humans; D017403:In Situ Hybridization; D051605:Kv Channel-Interacting Proteins; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; D051672:Shal Potassium Channels; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology
D002135:Calcium-Binding Proteins; C497018:KCND2 protein, human; C497021:KCND3 protein, human; C496752:KCNIP2 protein, human; C497019:Kcnd2 protein, mouse; C497022:Kcnd3 protein, mouse; C496755:Kcnip2 protein, mouse; D051605:Kv Channel-Interacting Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; D051672:Shal Potassium Channels; D011188:Potassium