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.
|Number of pages||9|
|State||Published - Jan 2014|
Bibliographical noteFunding 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
- Ion channel
- Juvenile-onset atrial fibrillation
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)