Genetic analysis for inherited arrhythmia and functional study using zebrafish model

• Project/Area Number: 26460670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kanazawa University
• Principal Investigator: Hayashi Kenshi 金沢大学, 附属病院, 助教 (00422642)
• Co-Investigator(Kenkyū-buntansha): 寳達 明彦 金沢大学, 医学系, 協力研究員 (00623662) ; 藤野 陽 金沢大学, 保健学系, 准教授 (40361993) ; 清水 渉 日本医科大学, 大学院医学研究科, 大学院教授 (50399606)
• Co-Investigator(Renkei-kenkyūsha): SEKINE Akihiro 京都大学, 医学系研究科, 教授 (30425631) ; AIBA Takeshi 独立行政法人国立循環器病研究センター, 循環器内科, 医長 (40574348)
• Research Collaborator: TSUDA Toyonobu ; TANAKA Yoshihiro
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ゼブラフィッシュ / 次世代シークエンス / モルフォリノ / Crispr/Cas9システム / 遺伝子改変ゼブラフィッシュ / 遺伝性不整脈 / 全エクソーム解析 / 次世代シークエンサー / 機能解析

Outline of Final Research Achievements

We performed genetic analysis using next generation sequencing for patients with inherited arrhythmia.We performed electrophysiological study for detected gene mutations in ion channel genes using patch clamp methods. We evaluated mutations in KCNH2 gene using zebrafish embryo. Knockdown or CRISPR-mediated deletions of the human LMNA ortholog, lmna in zebrafish recapitulated the electrophysiological phenotypes of human early-onset bradycardia.

Research Products

• [Int'l Joint Research] Birmingham University(米国)
• [Int'l Joint Research] Brigham and women’s hospital(英国)
• [Journal Article] Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models (2017)
  • Author(s): Kurata Y, Tsumoto K, Hayashi K, Hisatome I, Tanida M, Kuda Y, Shibamoto T
  • Journal Title: Am J Physiol Heart Circ Physiol Volume: 312 Issue: 1 Pages: H106-H127
  • DOI: 10.1152/ajpheart.00115.2016
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The genetics of atrial fibrillation. (2017)
  • Author(s): Hayashi K, Tada H, Yamagishi M.
  • Journal Title: Curr Opin Cardiol. Volume: 32 Pages: 10-16
  • Peer Reviewed
• [Journal Article] Impact of Updated Diagnostic Criteria for Long QT Syndrome on Clinical Detection of Diseased Patients: Results from Study of Patients Carrying Gene Mutations. (2016)
  • Author(s): Hayashi K, Konno T, Fujino N, Itoh H, Fujii Y, Imi-Hashida Y, Tada H, Tsuda T, Tanaka Y, Saito T, Ino H, Kawashiri M, Ohta K, Horie M, Yamagishi.M.
  • Journal Title: JACC Clin Electrophysiol Volume: 2 Issue: 3 Pages: 279-287
  • DOI: 10.1016/j.jacep.2016.01.003
  • Peer Reviewed
• [Journal Article] Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy. (2016)
  • Author(s): Nomura A, Tada H, Teramoto R, Konno T, Hodatsu A, Won HH, Kathiresan S, Ino H, Fujino N, Yamagishi M, Hayashi K.
  • Journal Title: J Cardiol. Volume: 2 Issue: 2 Pages: 133-9
  • DOI: 10.1016/j.jjcc.2015.09.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lipoprotein(a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin/Kexin Type 9 (<i>PCSK9</i>) Gain-of-Function Mutations (2016)
  • Author(s): Tada H, Kawashiri MA, Yoshida T, Teramoto R, Nohara A, Konno T, Inazu A, Mabuchi H, Yamagishi M, Hayashi K.
  • Journal Title: Circulation Journal Volume: 80 Issue: 2 Pages: 512-518
  • DOI: 10.1253/circj.CJ-15-0999
  • NAID: 130005120923
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Usefulness of Electrocardiographic Voltage to Determine Myocardial Fibrosis in Hypertrophic Cardiomyopathy. (2016)
  • Author(s): Konno T, Nagata Y, Teramoto R, Fujino N, Nomura A, Tada H, Sakata K, Furusho H, Takamura M, Nakamura H, Kawashiri MA, Yamagishi M, Hayashi K.
  • Journal Title: Am J Cardiol. Volume: 117 Issue: 3 Pages: 443-449
  • DOI: 10.1016/j.amjcard.2015.11.015
  • Peer Reviewed / Open Access
• [Journal Article] Right ventricular hypertrophy is associated with cardiovascular events in hypertrophic cardiomyopathy: evidence from study with magnetic resonance imaging. (2015)
  • Author(s): Nagata Y, Konno T, Fujino N, Hodatsu A, Nomura A, Hayashi K, Nakamura H, Kawashiri MA, Yamagishi M.
  • Journal Title: Can J Cardiol. Volume: 31 Issue: 6 Pages: 702-708
  • DOI: 10.1016/j.cjca.2014.12.036
  • Peer Reviewed / Open Access
• [Journal Article] Atrial fibrillation: an inherited cardiovascular disease-a commentary on genetics of atrial fibrillation: from families to genomes. (2015)
  • Author(s): Tada H, Kawashiri MA, Yamagishi M, Hayashi K.
  • Journal Title: J Hum Genet. Volume: 61 Issue: 1 Pages: 3-4
  • DOI: 10.1038/jhg.2015.63
  • Peer Reviewed / Open Access
• [Journal Article] Electrocardiographic QRS Fragmentation as a Marker for Myocardial Fibrosis in Hypertrophic Cardiomyopathy. (2015)
  • Author(s): Konno T, Hayashi K, Fujino N, Oka R, Nomura A, Nagata Y, Hodatsu A, Sakata K, Furusho H, Takamura M, Nakamura H, Kawashiri MA, Yamagishi M.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 26 Issue: 10 Pages: 1081-1087
  • DOI: 10.1111/jce.12742
  • Peer Reviewed / Open Access
• [Journal Article] Functional Characterization of Rare Variants Implicated in Susceptibility to Lone Atrial Fibrillation. (2015)
  • Author(s): Hayashi K, Konno T, Tada H, Tani S, Liu L, Fujino N, Nohara A, Hodatsu A, Tsuda T, Tanaka Y, Kawashiri MA, Ino H, Makita N, Yamagishi M.
  • Journal Title: Circ Arrhythm Electrophysiol. Volume: 8 Issue: 5 Pages: 1095-1104
  • DOI: 10.1161/circep.114.002519
  • Peer Reviewed / Open Access
• [Journal Article] High sensitivity of late gadolinium enhancement for predicting microscopic myocardial scarring in biopsied specimens in hypertrophic cardiomyopathy. (2014)
  • Author(s): Konno T，Hayashi K，Fujino N，Nagata Y，Hodatsu A，Masuta E，Sakata K，Nakamura H，Kawashiri M，Yamagishi M.
  • Journal Title: PLoS One. Volume: 9 Issue: 7 Pages: e101465-e101465
  • DOI: 10.1371/journal.pone.0101465
  • NAID: 120006460361
  • Peer Reviewed / Open Access
• [Journal Article] Compound heterozygosity deteriorates phenotypes of hypertrophic cardiomyopathy with founder MYBPC3 mutation: evidence from patients and zebrafish models. (2014)
  • Author(s): Hodatsu A, Konno T, Hayashi K, Funada A, Fujita T, Nagata Y, Fujino N, Kawashiri MA, Yamagishi M.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 307 Issue: 11 Pages: 1594-604
  • DOI: 10.1152/ajpheart.00637.2013
  • Peer Reviewed
• [Journal Article] Fragmented QRS Predicts Heart Failure Progression in Patients With Hypertrophic Cardiomyopathy (2014)
  • Author(s): Nomura A, Konno T, Fujita T, Tanaka Y, Nagata Y, Tsuda T, Hodatsu A, Sakata K, Nakamura H, Kawashiri MA, Fujino N, Yamagishi M, Hayashi K.
  • Journal Title: Circulation Journal Volume: 79 Issue: 1 Pages: 136-143
  • DOI: 10.1253/circj.CJ-14-0822
  • NAID: 130004704014
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] Exome Sequencing for Patients with Early-onset Cardiac Conduction Diseases (2017)
  • Author(s): Kenshi Hayashi, Akihiro Nomura, Yoshihiro Asano, Noboru Fujino, Kenji Sakata, Tetsuo Konno, Hayato Tada, Toyonobu Tsuda, Ryota Teramoto, Yoji Nagata, Yoshihiro Tanaka, Masa-aki Kawashiri, Calum MacRae, Seiji Takashima, Masakazu Yamagishi
  • Organizer: The 81st Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 金沢市
  • Year and Date: 2017-03-17
• [Presentation] Mechanisms of Fever-induced QT Prolongation in Patients with KCNH2 Mutations in the S5-pore Region: Evidence from Genotypic and Functional Analyses (2016)
  • Author(s): Kenshi Hayashi, Tadashi Nakajima, Yasutaka Kurata, Shoichi Tange, Noboru Fujino, Kenji Sakata, Tetsuo Konno, Toyonobu Tsuda, Yoji Nagata, Ryota Teramoto, Yoshihiro Tanaka, Takekatsu Saito, Masa-aki Kawashiri, Kunio Ohta, Yoshiaki Kaneko, Masahiko Kurabayash, Masakazu Yamagishi
  • Organizer: AHA 2016
  • Place of Presentation: New Orleans, LA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Updated Diagnostic Criteria for Long QT Syndrome (2016)
  • Author(s): Kenshi Hayashi, Tetsuo Konno, Noboru Fujino, Hideki Itoh, Yusuke Fujii, Yoko Imi-Hashida, Hayato Tada, Toyonobu Tsuda, Yoshihiro Tanaka, Takekatsu Saito, Hidekazu Ino, Masa-aki Kawashiri, Kunio Ohta, Minoru Horie, Masakazu Yamagishi.
  • Organizer: APHRS 2016
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-10-12
  • Int'l Joint Research
• [Presentation] The Role of Common and Rare Genetic Variants Implicated in Susceptibility to Atrial Fibrillation (2016)
  • Author(s): Kenshi Hayashi, Hayato Tada, and Masakazu Yamagishi
  • Organizer: APHRS 2016
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-10-12
  • Int'l Joint Research
• [Presentation] Hypertrophic Cardiomyopathy. (2015)
  • Author(s): Kenshi Hayashi, Noboru Fujino, Tetsuo Konno, Kenji Sakata, Takashi Fujita, Akihiko Hodatsu, Akihiro Nomura, Toyonobu Tsuda, Yoji Nagata, Yoshihiro Tanaka, Masa-aki Kawashiri, Masakazu Yamagishi.
  • Organizer: 2015 8TH APHRS SCIENTIFIC SESSIONS
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2015-11-19
  • Int'l Joint Research / Invited
• [Presentation] Mechanisms of Fever-induced QT Prolongation in Patients with KCNH2 Mutations in the S5-pore Region. (2015)
  • Author(s): Kenshi Hayashi, Tadashi Nakajima, Shoichi Tange, Noboru Fujino, Kenji Sakata, Tetsuo Konno, Toyonobu Tsuda, Yoshihiro Tanaka, Takekatsu Saito, Masa-aki Kawashiri, Kunio Ohta, Yoshiaki Kaneko, Masahiko Kurabayashi, Masakazu Yamagishi.
  • Organizer: ESC CONGRESS 2015
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] The role of common and rare genetic variants implicated in susceptibility to atrial fibrillation. (2015)
  • Author(s): Kenshi Hayashi, Hayato Tada, Masakazu Yamagishi.
  • Organizer: 2015 Annual Convention & Scientific Session of the Taiwan Society of Cardiology.
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-05-22
  • Int'l Joint Research / Invited
• [Presentation] Prognostic Significance of Sarcomere Gene Mutations and Myocardial Fibrosis in Hypertrophic Cardiomyopathy. (2014)
  • Author(s): Kenshi Hayashi, Noboru Fujino, Tetsuo Konno, Kenji Sakata, Takashi Fujita, Akihiko Hodatsu, Akihiro Nomura, Toyonobu Tsuda, Yoji Nagata, Yoshihiro Tanaka, Masa-aki Kawashiri, Masakazu Yamagishi.
  • Organizer: 7th Asia-Pacific Heart Rhythm Society Scientific Session
  • Place of Presentation: New Delhi, India
  • Year and Date: 2014-10-31
• [Presentation] Functional Characterization of Rare Variants Associated with Lone Atrial Fibrillation. (2014)
  • Author(s): Kenshi Hayashi, Noboru Fujino, Tetsuo Konno, Akihiko Hodatsu, Toyonobu Tsuda, Yoshihiro Tanaka, Masa-aki Kawashiri, Hidekazu Ino, and Masakazu Yamagishi.
  • Organizer: ESC CONGRESS 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-09-02
• [Book] 循環器ジャーナル (2017)
  • Author(s): 林 研至 山岸正和
  • Total Pages: 216
  • Publisher: 医学書院
• [Book] 遺伝性不整脈症候群 (2015)
  • Author(s): 林 研至 今野哲雄 川尻剛照 藤野陽 山岸正和
  • Total Pages: 4
  • Publisher: 南江堂
• [Book] 不整脈症候群 (2015)
  • Author(s): 林 研至、山岸正和
  • Total Pages: 4
  • Publisher: 南江堂
• [Remarks] 金沢大学循環器病態内科学ホームページ
  • URL: http://intmed2.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学大学院医学系研究科循環医科学専攻臓器機能制御学
  • URL: http://intmed2.w3.kanazawa-u.ac.jp/