A KCNQ1 mutation causes age-dependant bradycardia and persistent atrial fibrillation

  • Chang-Seok Ki
  • Chae Lim Jung
  • Hyun-ji Kim
  • Kwan-Hyuck Baek
  • Seung Jung Park
  • Young Keun On
  • Ki-Suk Kim
  • Su Jin Noh
  • Jae Boum Youm
  • June Soo KimEmail author
  • Hana ChoEmail author
Ion channels, receptors and transporters


Atrial fibrillation (AF) is the most common arrhythmia. Gain-of-function mutations in KCNQ1, the pore-forming α-subunit of the slow delayed rectifier K current (I Ks) channel, have been associated with AF. The purpose of this study was functional assessment of a mutation in KCNQ1 identified in a family with persistent AF and sinus bradycardia. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and bradycardia simultaneously in this family. Sanger sequencing in a family with hereditary persistent AF identified a novel KCNQ1 variant (V241F) in a highly conserved region of S4 domain. The proband and her son developed bradycardia and persistent AF in an age-dependent fashion. The other son was a mutation carrier but he showed sinus bradycardia and not AF. Whole-cell patch clamp electrophysiology showed that V241F mutation in KCNQ1 shifted the activation curve to the left and dramatically slowed deactivation, leading to a constitutively open-like phenotype. Computer modeling showed that V241F would slow pacemaker activity. Also, simulations of atrial excitation predicted that V241F results in extreme shortening of action potential duration, possibly resulting in AF. Our study indicates that V241F might cause sinus bradycardia by increasing I Ks. Additionally, V241F likely shortens atrial refractoriness to promote a substrate for reentry. KCNQ1 mutations have previously been described in AF, yet this is the first time a mutation in KCNQ1 is associated with age-dependent bradycardia and persistent AF. This finding further supports the hypothesis that sinus node dysfunction contributes to the development of AF.


Atrial fibrillation Bradycardia Electrophysiology Ion channel KCNQ1 Mutation 



This work was supported by the Samsung Biomedical Research Institute grant (SBRI #C-B0-206-3) and by the National Research Foundation of Korea (grant nos.: NRF-2012046878 and NRF-2013025108), funded by the Ministry of Science and Technology, Republic of Korea.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Chang-Seok Ki
    • 1
  • Chae Lim Jung
    • 1
  • Hyun-ji Kim
    • 3
  • Kwan-Hyuck Baek
    • 4
  • Seung Jung Park
    • 2
  • Young Keun On
    • 2
  • Ki-Suk Kim
    • 5
  • Su Jin Noh
    • 6
  • Jae Boum Youm
    • 6
  • June Soo Kim
    • 2
    Email author
  • Hana Cho
    • 3
    Email author
  1. 1.Departments of Laboratory Medicine and GeneticsSungkyunkwan University School of MedicineSeoulSouth Korea
  2. 2.Division of Cardiology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulSouth Korea
  3. 3.Department of Physiology, Samsung Biomedical Research InstituteSungkyunkwan University School of MedicineSuwonSouth Korea
  4. 4.Department of Molecular and Cellular Biology, Samsung Biomedical Research InstituteSungkyunkwan University School of MedicineSuwonSouth Korea
  5. 5.Next-generation pharmaceutical research center, Korea Institute of ToxicologyKRICTDaejeonSouth Korea
  6. 6.Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease CenterInje UniversityBusanSouth Korea

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