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J Mol Cell Cardiol. 2011 Jan;50(1):50-7. doi: 10.1016/j.yjmcc.2010.10.007. Epub 2010 Oct 13.

A KCR1 variant implicated in susceptibility to the long QT syndrome.

Author information

1
Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan. kenshi@med.kanazawa-u.ac.jp

Abstract

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.

PMID:
20950623
DOI:
10.1016/j.yjmcc.2010.10.007
[Indexed for MEDLINE]

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