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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.

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



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).


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


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.


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.


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


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

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