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

Kanae Hasegawa, Seiko Ohno, Takashi Ashihara, Hideki Itoh, Wei Guang Ding, Futoshi Toyoda, Takeru Makiyama, Hisaaki Aoki, Yoshihide Nakamura, Brian P. Delisle, Hiroshi Matsuura, Minoru Horie

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


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-I Ks, 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-I Ks conducted a large outward current induced by an atrial action potential waveform, and computer simulation incorporating the WT/G229D-I Ks 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.

Original languageEnglish
Pages (from-to)67-75
Number of pages9
JournalHeart Rhythm
Issue number1
StatePublished - Jan 2014

Bibliographical note

Funding Information:
This work was supported by Grants-in-Aid in Scientific Research from the Ministry of Education, Culture, Science, and Technology of Japan; a Health Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan; and Translational Research Funds from the Japan Circulation Society.


  • Atrial fibrillation
  • I
  • Ion channel
  • Juvenile-onset atrial fibrillation
  • KCNQ1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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