A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels

Heart Rhythm. 2014 Jan;11(1):67-75. doi: 10.1016/j.hrthm.2013.09.073. Epub 2013 Oct 1.


Background: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias. In some patients, the disease is inheritable; however, hereditary aspects of AF remain not fully elucidated.

Objective: The purpose of this study was to identify genetic backgrounds that contribute to juvenile-onset AF and to define the mechanism.

Methods: In 30 consecutive juvenile-onset AF patients (onset age <50 years), we screened AF-related genes (KCNQ1, KCNH2, KCNE1-3, KCNE5, KCNJ2, SCN5A). We analyzed the function of mutant channels using whole-cell patch-clamp techniques and computer simulations.

Results: Among the juvenile-onset AF patients, we identified three mutations (10%): SCN5A-M1875T, KCNJ2-M301K, and KCNQ1-G229D. Because KCNQ1 variant (G229D) identified in a 16-year-old boy was novel, we focused on the proband. The G229D-IKs was found to induce a large instantaneous activating component without deactivation after repolarization to -50 mV. In addition, wild-type (WT)/G229D-IKs (WT and mutant coexpression) displayed both instantaneous and time-dependent activating currents. Compared to WT-IKs, the tail current densities in WT/G229D-IKs were larger at test potentials between -130 and -40 mV but smaller at test potentials between 20 and 50 mV. Moreover, WT/G229D-IKs resulted in a negative voltage shift for current activation (-35.2 mV) and slower deactivation. WT/G229D-IKs conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-IKs results revealed that the mutation shortened atrial but not ventricular action potential.

Conclusion: A novel KCNQ1-G229D mutation identified in a juvenile-onset AF patient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF.

Keywords: AF; AP; Atrial fibrillation; CHO; Chinese hamster ovary; ECG; I(Ks); Ion channel; Juvenile-onset atrial fibrillation; KCNQ1; QTc; WT; action potential; atrial fibrillation; corrected QT interval; electrocardiogram; wild type.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / physiopathology
  • Computer Simulation
  • DNA / genetics*
  • DNA Mutational Analysis
  • Electrocardiography
  • Genotype
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • KCNQ1 Potassium Channel / metabolism
  • Male
  • Mutation, Missense*
  • Patch-Clamp Techniques
  • Potassium Channels, Voltage-Gated / genetics*
  • Potassium Channels, Voltage-Gated / metabolism


  • KCNQ1 Potassium Channel
  • Potassium Channels, Voltage-Gated
  • DNA