Kanae Hasegawa1, Seiko Ohno2, Takashi Ashihara2, Hideki Itoh2, Wei-Guang Ding3, Futoshi Toyoda3, Takeru Makiyama4, Hisaaki Aoki5, Yoshihide Nakamura5, Brian P Delisle6, Hiroshi Matsuura3, Minoru Horie7. 1. Department of Cardiovascular Biology and Medicine, Niigata University School of Medical and Dental Sciences, Niigata, Japan; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. 2. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. 3. Department of Physiology, Shiga University of Medical Science, Otsu, Japan. 4. Department of Cardiovascular and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. 5. Department of Pediatrics, Kinki University Faculty Medicine, Osaka, Japan. 6. Department of Physiology, University of Kentucky, Lexington, Kentucky. 7. Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. Electronic address: horie@belle.shiga-med.ac.jp.
Abstract
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.
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 AFpatients (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 AFpatients, 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 AFpatient altered the IKs activity and kinetics, thereby increasing the arrhythmogenicity to AF.
Authors: Dandan Yang; Xiaoping Wan; Adrienne T Dennis; Emre Bektik; Zhihua Wang; Mauricio G S Costa; Charline Fagnen; Catherine Vénien-Bryan; Xianyao Xu; Daniel H Gratz; Thomas J Hund; Peter J Mohler; Kenneth R Laurita; Isabelle Deschênes; Ji-Dong Fu Journal: Circulation Date: 2021-02-16 Impact factor: 29.690