A KCR1 variant implicated in susceptibility to the long QT syndrome.
The acquired long QT syndrome (aLQTS) is frequently associated with extrinsic and intrinsic risk factors including therapeutic agents that inadvertently inhibit the KCNH2 K(+) channel that underlies the repolarizing I(Kr) current in the heart. Previous reports demonstrated that K(+) channel regulator 1 (KCR1) diminishes KCNH2 drug sensitivity and may protect susceptible patients from developing aLQTS. Here, we describe a novel variant of KCR1 (E33D) isolated from a patient with ventricular fibrillation and significant QT prolongation. We recorded the KCNH2 current (I(KCNH2)) from CHO-K1 cells transfected with KCNH2 plus wild type (WT) or mutant KCR1 cDNA, using whole cell patch-clamp techniques and assessed the development of I(KCNH2) inhibition in response to well-characterized KCNH2 inhibitors. Unlike KCR1 WT, the E33D variant did not protect KCNH2 from the effects of class I antiarrhythmic drugs such as quinidine or class III antiarrhythmic drugs including dofetilide and sotalol. The remaining current of the KCNH2 WT+KCR1 E33D channel after 100 pulses in the presence of each drug was similar to that of KCNH2 alone. Simulated conditions of hypokalemia (1mM [K(+)](o)) produced no significant difference in the fraction of the current that was protected from dofetilide inhibition with KCR1 WT or E33D. The previously described α-glucosyltransferase activity of KCR1 was found to be compromised in KCR1 E33D in a yeast expression system. Our findings suggest that KCR1 genetic variations that diminish the ability of KCR1 to protect KCNH2 from inhibition by commonly used therapeutic agents constitute a risk factor for the aLQTS.
Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan. kenshi@med.kanazawa-u.ac.jp
Kenshi
K
Hayashi
Noboru
N
Fujino
Hidekazu
H
Ino
Katsuharu
K
Uchiyama
Kenji
K
Sakata
Tetsuo
T
Konno
Eiichi
E
Masuta
Akira
A
Funada
Yuichiro
Y
Sakamoto
Toshinari
T
Tsubokawa
Akihiko
A
Hodatsu
Toshihiko
T
Yasuda
Honin
H
Kanaya
Min Young
MY
Kim
Sabina
S
Kupershmidt
Haruhiro
H
Higashida
Masakazu
M
Yamagishi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005260:Female; D005816:Genetic Complementation Test; D005964:Glucosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D029701:Saccharomyces cerevisiae Proteins; C518821:ALG10B protein, human; C113849:DIE2 protein, S cerevisiae; D005964:Glucosyltransferases