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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cyclic AMP-Dependent Protein Kinases / genetics*
  • Electrocardiography
  • Exercise Test
  • Female
  • Genotype
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Phenotype
  • Phosphorylation
  • Retrospective Studies
  • Romano-Ward Syndrome / genetics*


  • KCNQ1 Potassium Channel
  • Cyclic AMP-Dependent Protein Kinases