Noriaki Yamada1, Yoshihiro Asano1, Masashi Fujita2, Satoru Yamazaki3, Atsushi Inanobe4, Norio Matsuura5, Hatasu Kobayashi6, Seiko Ohno7,8, Yusuke Ebana9, Osamu Tsukamoto10, Saki Ishino11, Ayako Takuwa1, Hidetaka Kioka1, Toru Yamashita12, Norio Hashimoto12, Dimitar P Zankov13, Akio Shimizu13, Masanori Asakura14, Hiroshi Asanuma15, Hisakazu Kato10, Yuya Nishida10, Yohei Miyashita1, Haruki Shinomiya1, Nobu Naiki16, Kenshi Hayashi17, Takeru Makiyama18, Hisakazu Ogita13, Katsuyuki Miura8,19, Hirotsugu Ueshima8,19, Issei Komuro20, Masakazu Yamagishi17,21, Minoru Horie8,16, Koichi Kawakami22,23, Tetsushi Furukawa24, Akio Koizumi25, Yoshihisa Kurachi4, Yasushi Sakata1, Tetsuo Minamino26, Masafumi Kitakaze27, Seiji Takashima10. 1. Departments of Cardiovascular Medicine (N.Y., Y.A., A.T., H. Kioka, Y.M., H.S., Y.S.), Osaka University Graduate School of Medicine, Suita, Japan. 2. Department of Onco-cardiology, Osaka International Cancer Institute, Japan (M.F.). 3. Departments of Cell Biology (S.Y.), National Cerebral and Cardiovascular Center, Suita, Japan. 4. Pharmacology (A.I., Y.K.), Osaka University Graduate School of Medicine, Suita, Japan. 5. Departments of Health and Environmental Sciences (N.M.), Kyoto University Graduate School of Medicine, Japan. 6. Department of Biomedical Sciences, College of Life and Health Sciences Chubu University, Kasugai, Japan (H. Kobayashi). 7. Bioscience and Genetics (S.O.), National Cerebral and Cardiovascular Center, Suita, Japan. 8. Center for Epidemiologic Research in Asia (S.O., K.M., H.U., M.H.), Shiga University of Medical Science, Otsu, Japan. 9. Life Science and Bioethics Research Center (Y.E.), Tokyo Medical and Dental University, Japan. 10. Medical Biochemistry (O.T., H. Kato, Y.N., S.T.), Osaka University Graduate School of Medicine, Suita, Japan. 11. Center of Medical Innovation and Translational Research (S.I.), Osaka University Graduate School of Medicine, Suita, Japan. 12. Pharmaceuticals Division, Nissan Chemical Corporation, Tokyo, Japan (T.Y., N.H.). 13. Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology (D.P.Z., A.S., H.O.), Shiga University of Medical Science, Otsu, Japan. 14. Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan (M.A.). 15. Department of Internal Medicine, Meiji University of Integrative Medicine, Nantan, Japan (H.A.). 16. Departments of Cardiovascular Medicine (N.N., M.H.), Shiga University of Medical Science, Otsu, Japan. 17. Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan (K.H., M.Y.). 18. Cardiovascular Medicine (T. Makiyama), Kyoto University Graduate School of Medicine, Japan. 19. Public Health (K.M., H.U.), Shiga University of Medical Science, Otsu, Japan. 20. Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine, Japan (I.K.). 21. Department of Human Sciences, Osaka University of Human Sciences, Settsu, Japan (M.Y.). 22. Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan (K.K.). 23. Department of Genetics, SOKENDAI (The Graduate University for Advanced Studies), Mishima, Japan (K.K.). 24. Department of Bioinformational Pharmacology (T.F.), Tokyo Medical and Dental University, Japan. 25. Public Interest Foundation Kyoto Hokenkai, Japan (A.K.). 26. Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Japan (T. Minamino). 27. Clinical Medicine and Development (M.K.), National Cerebral and Cardiovascular Center, Suita, Japan.
Abstract
BACKGROUND: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.
BACKGROUND:Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. METHODS: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. RESULTS: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant humanKCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.
Authors: Bianca J J M Brundel; Xun Ai; Mellanie True Hills; Myrthe F Kuipers; Gregory Y H Lip; Natasja M S de Groot Journal: Nat Rev Dis Primers Date: 2022-04-07 Impact factor: 52.329
Authors: Feng Zhang; Guang Hai Zhou; Qi An; Jie Yang; Yu Hao Wang; Jia Quan Zhu; Song Nan Jin; Jin Fu Wen Journal: Int J Clin Exp Pathol Date: 2022-03-15
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Back Sternick Eduardo; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong-Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti Mac Intyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Pablo Ochoa Juan; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: J Arrhythm Date: 2022-05-31
Authors: Jeffrey D Steimle; Francisco J Grisanti Canozo; Minjun Park; Zachary A Kadow; Md Abul Hassan Samee; James F Martin Journal: JCI Insight Date: 2022-06-08
Authors: Arthur A M Wilde; Christopher Semsarian; Manlio F Márquez; Alireza Sepehri Shamloo; Michael J Ackerman; Euan A Ashley; Eduardo Back Sternick; Héctor Barajas-Martinez; Elijah R Behr; Connie R Bezzina; Jeroen Breckpot; Philippe Charron; Priya Chockalingam; Lia Crotti; Michael H Gollob; Steven Lubitz; Naomasa Makita; Seiko Ohno; Martín Ortiz-Genga; Luciana Sacilotto; Eric Schulze-Bahr; Wataru Shimizu; Nona Sotoodehnia; Rafik Tadros; James S Ware; David S Winlaw; Elizabeth S Kaufman; Takeshi Aiba; Andreas Bollmann; Jong Il Choi; Aarti Dalal; Francisco Darrieux; John Giudicessi; Mariana Guerchicoff; Kui Hong; Andrew D Krahn; Ciorsti MacIntyre; Judith A Mackall; Lluís Mont; Carlo Napolitano; Juan Pablo Ochoa; Petr Peichl; Alexandre C Pereira; Peter J Schwartz; Jon Skinner; Christoph Stellbrink; Jacob Tfelt-Hansen; Thomas Deneke Journal: Europace Date: 2022-09-01 Impact factor: 5.486
Authors: Pietro Mesirca; Vadim V Fedorov; Thomas J Hund; Angelo G Torrente; Isabelle Bidaud; Peter J Mohler; Matteo E Mangoni Journal: Annu Rev Pharmacol Toxicol Date: 2020-10-05 Impact factor: 13.820