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Heart Rhythm. 2014 Mar;11(3):459-68. doi: 10.1016/j.hrthm.2013.11.021. Epub 2013 Nov 21.

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation.

Author information

1
Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky.
2
Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota.
3
Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Sciences, Seta-tsukinowa, Otsu, Japan.
4
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
5
Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, Kentucky. Electronic address: brian.delisle@uky.edu.

Abstract

BACKGROUND:

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 channel that conducts the slowly activating component of the delayed rectifier K(+) current (IKs). Clinically, the diagnosis of LQT1 is complicated by variable phenotypic expressivity, whereby approximately 25% of genotype-positive individuals present with concealed LQT1 (resting corrected QT [QTc] interval ≤460 ms).

OBJECTIVE:

To determine whether a specific molecular mechanism contributes to concealed LQT1.

METHODS:

We identified a multigenerational LQT1 family whereby 79% of the patients genotype-positive for p.Ile235Asn-KCNQ1 (I235N-Kv7.1) have concealed LQT1. We assessed the effect I235N-Kv7.1 has on IKs and the ventricular action potential (AP) by using in vitro analysis and computational simulations.

RESULTS:

Clinical data showed that all 10 patients with I235N-Kv7.1 have normal resting QTc intervals but abnormal QTc interval prolongation during the recovery phase of an electrocardiographic treadmill stress test. Voltage-clamping HEK293 cells coexpressing wild-type Kv7.1 and I235N-Kv7.1 (to mimic the patients' genotypes) showed that I235N-Kv7.1 generated relatively normal functioning Kv7.1 channels but were insensitive to protein kinase A (PKA) activation. Phosphomimetic and quinidine sensitivity studies suggest that I235N-Kv7.1 limits the conformational changes in Kv7.1 channels, which are necessary to upregulate IKs after PKA phosphorylation. Computational ventricular AP simulations predicted that the PKA insensitivity of I235N-Kv7.1 is primarily responsible for prolonging the AP with β-adrenergic stimulation, especially at slower cycle lengths.

CONCLUSIONS:

KCNQ1 mutations that generate relatively normal Kv7.1 channels, but limit the upregulation of IKs by PKA activation, likely contribute to concealed LQT1.

KEYWORDS:

I(Ks); KCNQ1; Kv7.1; Long QT syndrome; PKA activation; Treadmill stress test

PMID:
24269949
PMCID:
PMC4333640
DOI:
10.1016/j.hrthm.2013.11.021
[Indexed for MEDLINE]
Free PMC Article

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