Clarification of molecular mechanisms and establishment of appropriate therapies for atypical inherited arrhythmia syndromes
Project/Area Number |
17K09487
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Cardiovascular medicine
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Research Institution | Gunma University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
倉林 正彦 群馬大学, 大学院医学系研究科, 教授 (00215047)
金古 善明 群馬大学, 大学院医学系研究科, 准教授 (60302478)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Keywords | 遺伝性不整脈 / 次世代シークエンス / イオンチャネル / 構造-機能連関 / 心脳チャネル病 / 遺伝性不整脈症候群 / 次世代シークエンサー / 機能解析 / 遺伝性不整脈疾患 / 分子病態 / 遺伝子変異特異的治療 |
Outline of Final Research Achievements |
In patients with inherited arrhythmia syndromes (IASs) exhibiting unique or various phenotypes, optimal therapies have not been established. We sought to identify their responsible mutations using next generation sequencing (NGS), and reveal their pathophysiology using patch-clamp techniques. 1. We identified a novel RYR2 deletion in a family with atypical CPVT by focusing on read numbers of NGS, which help us provide an optimal therapy. 2. We revealed that SCN5A mutations (N1541D and R1632C) identified in patients with various phenotypes exhibited enhanced closed-state inactivation but through different mechanisms. 3. We encountered teenage siblings exhibiting both cardiac (ERS and PAF) and cerebral(epilepsy) phenotypes, in whom we identified a KCND3 V392I mutation with a mixed electrophysiological phenotype. Our data will provide novel insights into structure-function relationships of ion channels, and lead to establish optimal therapies for IASs with unique or various phenotypes.
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Academic Significance and Societal Importance of the Research Achievements |
我々は、病態が未解明で治療法も未確立の特異及び多彩な表現型を呈する遺伝性不整脈症候群において、遺伝子変異を同定し、さらに機能解析を行うことにより、病態を解明し得た。これらの研究成果は、臨床面では最適な治療法を確立し、さらに新規治療法の基礎を構築することにつながる可能性がある。一方、基礎研究面ではイオンチャネルの構造-機能連関に新たな知見をもたらすなど、多方面に派生する可能性がある。
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Report
(4 results)
Research Products
(33 results)
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[Journal Article] Atypical Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Utilizing a Slow Pathway Extending to the Inferolateral Right Atrium2019
Author(s)
Kaneko Y, Nakajima T, Nogami A, Inden Y, Asakawa T, Morishima I, Mizukami A, Iizuka T, Tamura S, Ota C, Kanzaki Y, Nakagawa K, Suzuki M, Kurabayashi M.
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Journal Title
Circulation Reports
Volume: 1
Issue: 2
Pages: 46-54
DOI
NAID
ISSN
2434-0790
Year and Date
2019-02-08
Related Report
Peer Reviewed
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[Presentation] Epinephrine-induced marked QT prolongation in patients with type-3 long QT syndrome.2018
Author(s)
Tadashi Nakajima, Yoshiaki Kaneko, Reika Kawabata, Takashi Iizuka, Shuntato Tamura, Yukie Sano, Hiroshi Hasegawa, Tadanobu Irie, Yoshiaki Ohyama,Yoshinao Sugai, Koji Kumagai, Shigeto Naito, Masahiko Nishiyama, Masahiko Kurabayashi.
Organizer
11th Asia Pacific Heart Rhythm Society Scientific Session
Related Report
Int'l Joint Research
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[Presentation] Rare Coding Variants in Genes Other Than SCN5A Are Minimal Genetic Burden on the Prognosis of Brugada Syndrome.2018
Author(s)
Isikawa T, Mishima H, Ohno S, Aiba T, Nakano Y, Aizawa Y, Nakajima T, Hayashi K, Murakoshi N, Yagihara N, Kimoto H, Makiyama T, Watanabe H, Morita H, Yoshiura K, Nogami A, Shimizu W, Horie M, Tanaka T, Makita N.
Organizer
第65回日本不整脈心電学会学術大会
Related Report
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[Presentation] Diverse Precipitating Factors in Secondary Long QT Syndrome.2018
Author(s)
Tadashi Nakajima, Yoshiaki Kaneko, Takashi Sakai, Shuntaro Tamura, Takashi Iizuka, Tadanobu Irie, Tommy Dharmawan, Michiko Imai, Nogiku Niwamae, Shoichi Tange, Masahiko Kurabayashi.
Organizer
第82回日本循環器学会学術集会.
Related Report
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[Presentation] Divergent Molecular Mechanisms of Cardiac Sodium Cannelopathies Exhibiting Brugada Syndrome with Multiple Electrophysiological Phenotypes.2018
Author(s)
Tommy Dharmawan, Tadashi Nakajima, Takashi Iizuka, Takashi Sasaki, Shuntaro Tamura, Tadanobu Irie, Hiroki Matsui, Michiko Imai, Nogiku Niwamae, Shoichi Tange, Yoshiaki Kaneko, Masahiko Kurabayashi.
Organizer
第82回日本循環器学会学術集会.
Related Report
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[Presentation] Identification of clinical characteristics and genetic variants that predispose patients with vasospastic angina to ventricular tachyarrhythmias.2017
Author(s)
Tadashi Nakajima, Yoshiaki Kaneko, Yohei Ono, Akihiro Saito, Michiko Imai, Takashi Iizuka, Tadanobu Irie, Tommy Dharmawan, Ryuichi Funada, Noriaki Takama, Shu Kasama, Kohki Nakamura, Nogiku Niwamae, Shoichi Tange, Masahiko Kurabayashi.
Organizer
APHRS 2017/JHRS 2017.
Related Report
Int'l Joint Research
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[Presentation] The clinical and genetic predispositions to ventricular tachyarrhythmias associated with vasospastic angina.2017
Author(s)
Tadashi Nakajima, Yohei Ono, Yoshiaki Kaneko, Akihiro Saito, Michiko Imai, Takashi Iizuka, Tadanobu Irie, Ryuichi Funada, Noriaki Takama, Shu Kasama, Kohki Nakamura, Nogiku Niwamae, Shoichi Tange, Masahiko Kurabayashi.
Organizer
ESC Congress 2017.
Related Report
Int'l Joint Research