特異及び多彩な表現型を呈する遺伝性不整脈疾患の分子病態の解明と治療法の確立

• 研究課題/領域番号: 17K09487
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 循環器内科学
• 研究機関: 群馬大学
• 研究代表者: 中島 忠 群馬大学, 医学部附属病院, 講師 (40510574)
• 研究分担者: 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)
• 研究期間 (年度): 2017-04-01 – 2020-03-31
• 研究課題ステータス: 完了 (2019年度)
• 配分額: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2019年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円); 2018年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円); 2017年度: 1,820千円 (直接経費: 1,400千円、間接経費: 420千円)
• キーワード: 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

研究成果の概要

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、次世代シークエンス(NGS)を駆使し遺伝子変異を同定し、機能解析を行い分子病態を解明し、治療法の基礎を構築すべく研究を行った。その結果、①特異な表現型を呈するカテコラミン誘発性多形性心室頻拍家系において、NGSでリード数に着目し、新規RYR2欠失変異を同定、②多彩な表現型を呈するSCN5A N1541D及びR1632C変異において、closed-state inactivation増強のメカニズムが異なることを解明、③心臓と脳の表現型を呈する姉妹にKCND3 V392Iを同定し、新規心脳チャネル病を提唱、などの成果を得た。

研究成果の学術的意義や社会的意義

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。

研究成果

• [雑誌論文] Biophysical defects of an SCN5A V1667I mutation associated with epinephrine-induced marked QT prolongation. (2020)
  • 著者名/発表者名: Nakajima T, Dharmawan T, Kawabata-Iwakawa R, Tamura S, Hasegawa H, Kobari T, Kaneko Y, Nishiyama M, Kurabayashi M.
  • 雑誌名: J Cardiovasc Electrophysiol 巻: -
  • 査読あり
• [雑誌論文] Atypical Fast-Slow Atrioventricular Nodal Reentrant Tachycardia Utilizing a Slow Pathway Extending to the Inferolateral Right Atrium (2019)
  • 著者名/発表者名: 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.
  • 雑誌名: Circulation Reports 巻: 1 号: 2 ページ: 46-54
  • DOI: 10.1253/circrep.CR-18-0016
  • NAID: 130007596358
  • ISSN: 2434-0790
  • 年月日: 2019-02-08
  • 査読あり
• [雑誌論文] Role of the voltage sensor module in Nav domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation. (2019)
  • 著者名/発表者名: Nakajima T, Kaneko Y, Dharmawan T, Kurabayashi M.
  • 雑誌名: Channels 巻: 13 号: 1 ページ: 331-343
  • DOI: 10.1080/19336950.2019.1649521
  • 査読あり / オープンアクセス
• [雑誌論文] Enhanced closed-state inactivation of mutant cardiac sodium channels (SCN5A N1541D and R1632C) through different mechanisms (2019)
  • 著者名/発表者名: Dharmawan Tommy、Nakajima Tadashi、Iizuka Takashi、Tamura Shuntaro、Matsui Hiroki、Kaneko Yoshiaki、Kurabayashi Masahiko
  • 雑誌名: Journal of Molecular and Cellular Cardiology 巻: 130 ページ: 88-95
  • DOI: 10.1016/j.yjmcc.2019.03.023
  • 査読あり
• [雑誌論文] Identification of a novel exon3 deletion of RYR2 in a family with catecholaminergic polymorphic ventricular tachycardia (2019)
  • 著者名/発表者名: Dharmawan T, Nakajima T, Ohno S, Iizuka T, Tamura S, Kaneko Y, Horie M, Kurabayashi M.
  • 雑誌名: Ann Noninvasive Electrocardiol 巻: - 号: 3
  • DOI: 10.1111/anec.12623
  • 査読あり / オープンアクセス
• [雑誌論文] What is the mechanism of wide QRS tachycardia? (2019)
  • 著者名/発表者名: Kaneko Y, Nakajima T, Iizuka T, Tamura S, Kurabayashi M.
  • 雑誌名: Pacing Clin Electrophysiol 巻: 印刷中 号: 6 ページ: 725-727
  • DOI: 10.1111/pace.13687
  • 査読あり
• [雑誌論文] A case of atypical fast-slow atrioventricular nodal reentrant tachycardia utilizing a slow pathway extending to the superoanterior right atrium. (2019)
  • 著者名/発表者名: Kaneko Y, Nakajima T, Iizuka T, Tamura S, Kurabayashi M.
  • 雑誌名: Int Heart J 巻: 印刷中
  • 査読あり
• [雑誌論文] Atrioventricular Block-induced Torsades de Pointes Associated with <i>KCNQ1</i>-G269S (2018)
  • 著者名/発表者名: Nakajima T, Sugawara T, Kaneko Y, Kurabayashi M.
  • 雑誌名: Internal Medicine 巻: 57 号: 6 ページ: 905-906
  • DOI: 10.2169/internalmedicine.9372-17
  • NAID: 130006507383
  • ISSN: 0918-2918, 1349-7235
  • 査読あり
• [雑誌論文] Atrial and ventricular activation sequence after ventricular induction/entrainment pacing during fast-slow atrioventricular nodal reentrant tachycardia: New insight into the use of V-A-A-V for the differential diagnosis of supraventricular tachycardia. (2017)
  • 著者名/発表者名: Kaneko Y, Nakajima T, Irie T, Iizuka T, Tamura S, Kurabayashi M.
  • 雑誌名: Heart Rhythm 巻: 14 号: 11 ページ: 1615-1622
  • DOI: 10.1016/j.hrthm.2017.06.006
  • 査読あり
• [学会発表] Enhanced closed-state inactivation of overlapped phenotype-associated mutant cardiac sodium channels (SCN5A N1541D and R1632C) through different biophysical mechanisms. (2019)
  • 著者名/発表者名: Tadashi Nakajima, Tommy Dharmawan, Takashi Iizuka, Shuntaro Tamura, Hiroshi Hasegawa, Yoshiaki Kaneko, Masahiko Kurabayashi.
  • 学会等名: The 66th Annual Meeting of the Japanese Heart Rhythm Society
• [学会発表] VA linking after atrial entrainment of typical fast-slow atrioventricular nodal reentrant tachycardia is masked depending on the pacing rate. (2019)
  • 著者名/発表者名: Yoshiaki Kaneko, Tadashi Nakajima, Takashi Iizuka, Shuntaro Tamura, Masahiko Kurabayashi.
  • 学会等名: Heart Rhythm 2019
  • 国際学会
• [学会発表] Does a RYR2 K4392R Variant Act as a Genetic Modifier for Arrhythmic Phenotypes in Distinct Disease Entities of Inherited Arrhythmia Syndromes? (2019)
  • 著者名/発表者名: Tadashi Nakajima, Yoshiaki Kaneko, Takashi Iizuka, Shuntato Tamura, Hiroshi Hasegawa, Tommy Dharmawan, Masaki Ota, Kentaro Ikeda, Masahiko Kurabayashi.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] A Pedigree of Type-3 Long QT Syndrome Exhibiting Epinephrine-Induced Marked QT Prolongation. (2019)
  • 著者名/発表者名: Tadashi Nakajima, Yoshiaki Kaneko, Takashi Iizuka, Shuntato Tamura, Hiroshi Hasegawa, Tommy Dharmawan, Masahiko Kurabayashi.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] Enhanced Closed-State Fast Inactivation of Cardiac Sodium Channels as a Primary Biophysical Defect Associated with an SCN5A Channelopathy. (2019)
  • 著者名/発表者名: Tommy Dharmawan, Tadashi Nakajima, Takashi Iizuka, Shuntaro Tamura, Hiroki Matsui, Yoshiaki Kaneko, Masahiko Kurabayashi.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] New appearance of J wave after the onset of myocardial infarction is associated with a poor prognosis. (2019)
  • 著者名/発表者名: Shuntaro Tamura, Yoshiaki Kaneko, Tadashi Nakajima, Takashi Iizuka, Masahiko Kurabayashi.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] Differential atrial entrainment pacing predicts ablation site for successfully curing slow-fast atrioventricular nodal reentrant tachycardia. (2019)
  • 著者名/発表者名: Takashi Iizuka, Yoshiaki Kaneko, Tadashi Nakajima, Shuntaro Tamura, Masahiko Kurabayashi, Shiro Nakahara.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] A new phenotype of superior type fast-slow atrioventricular nodal reentrant tachycardia mimicking slow-fast type. (2019)
  • 著者名/発表者名: Takashi Iizuka, Yoshiaki Kaneko, Tadashi Nakajima, Shuntaro Tamura, Masahiko Kurabayashi.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] VA linking after atrial entrainment of typical fast-slow atrioventricular nodal reentrant tachycardia is masked depending on the pacing rate. (2019)
  • 著者名/発表者名: Yoshiaki Kaneko, Tadashi Nakajima, Takashi Iizuka, Shuntaro Tamura, Masahiko Kurabayashi.
  • 学会等名: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [学会発表] Epinephrine-induced marked QT prolongation in patients with type-3 long QT syndrome. (2018)
  • 著者名/発表者名: 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.
  • 学会等名: 11th Asia Pacific Heart Rhythm Society Scientific Session
  • 国際学会
• [学会発表] Application of V-A-A-V Response Immediately after Ventricular Induction/Entrainment to Discriminate Atypical Atrioventricular Nodal Reentrant Tachycardia from Atrial Tachycardia. (2018)
  • 著者名/発表者名: Yoshiaki Kaneko, Tadashi Nakajima, Takashi Iizuka, Shuntaro Tamura, Masahiko Kurabayashi.
  • 学会等名: 11th Asia Pacific Heart Rhythm Society Scientific Session
  • 国際学会
• [学会発表] Novel Electrophysiological Evidence of Functionally Longitudinal Dissociation in the His Bundle: Paradoxical Penetration into AV Node During Ventricular Stimulation. (2018)
  • 著者名/発表者名: Shuntaro Tamura, Yoshiaki Kaneko, Tadashi Nakajima, Takashi Iizuka, Masahiko Kurabayashi.
  • 学会等名: 第65回日本不整脈心電学会学術大会
• [学会発表] Atypical Fast-slow Atrioventricular Nodal Reentrant Tachycardia Apparently Mimicking Slow-fast Type due to Block at the Lower Common Pathway. (2018)
  • 著者名/発表者名: Takashi Iizuka, Yoshiaki Kaneko, Tadashi Nakajima, Tadanobu Irie, Shuntaro Tamura, Masahiko Kurabayashi.
  • 学会等名: 第65回日本不整脈心電学会学術大会
• [学会発表] Hypertrabeculation localized at left ventricular apex may be associated with life-threatening ventricular arrhythmias in Brugada Syndrome. (2018)
  • 著者名/発表者名: Tadashi Nakajima, Yoshiaki Kaneko, Koji Kurosawa, Shuntaro Tamura, Takashi Iizuka, Tadanobu Irie, Masahiko Kurabayashi.
  • 学会等名: 第65回日本不整脈心電学会学術大会
• [学会発表] Rare Coding Variants in Genes Other Than SCN5A Are Minimal Genetic Burden on the Prognosis of Brugada Syndrome. (2018)
  • 著者名/発表者名: 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.
  • 学会等名: 第65回日本不整脈心電学会学術大会
• [学会発表] Uncommon phenotype of catecholaminergic ventricular tachycardia presenting with prominent U-waves. (2018)
  • 著者名/発表者名: Tommy Dharmawan, Tadashi Nakajima, Seiko Ohno, Takashi Iizuka, Tadanobu Irie, Yoshiaki Kaneko, Minoru Horie, Masahiko Kurabayashi.
  • 学会等名: Heart Rhythm Society Scientific Sessions 2018
  • 国際学会
• [学会発表] Uncommon phenotype of catecholaminergic polymorphic ventricular tachycardia presenting with prominent U-waves. (2018)
  • 著者名/発表者名: Tommy Dharmawan, Tadashi Nakajima, Seiko Ohno, Takashi Iizuka, Tadanobu Irie, Yoshiaki Kaneko, Minoru Horie, Masahiko Kurabayashi.
  • 学会等名: Heart Rhythm 2018.
  • 国際学会
• [学会発表] Diverse Precipitating Factors in Secondary Long QT Syndrome. (2018)
  • 著者名/発表者名: Tadashi Nakajima, Yoshiaki Kaneko, Takashi Sakai, Shuntaro Tamura, Takashi Iizuka, Tadanobu Irie, Tommy Dharmawan, Michiko Imai, Nogiku Niwamae, Shoichi Tange, Masahiko Kurabayashi.
  • 学会等名: 第82回日本循環器学会学術集会.
• [学会発表] Hypertraveculation at Left Ventricular Apex is Highly Prevalent and may be Associated with Life-Threatening Ventricular Arrhythmias in Brugada Syndrome. (2018)
  • 著者名/発表者名: 中島 忠、金古善明、黒沢幸嗣、田村峻太郎、飯塚貴士、Tommy Dharmawan、入江忠信、倉林正彦.
  • 学会等名: 第82回日本循環器学会学術集会.
• [学会発表] Divergent Molecular Mechanisms of Cardiac Sodium Cannelopathies Exhibiting Brugada Syndrome with Multiple Electrophysiological Phenotypes. (2018)
  • 著者名/発表者名: Tommy Dharmawan, Tadashi Nakajima, Takashi Iizuka, Takashi Sasaki, Shuntaro Tamura, Tadanobu Irie, Hiroki Matsui, Michiko Imai, Nogiku Niwamae, Shoichi Tange, Yoshiaki Kaneko, Masahiko Kurabayashi.
  • 学会等名: 第82回日本循環器学会学術集会.
• [学会発表] Identification of clinical characteristics and genetic variants that predispose patients with vasospastic angina to ventricular tachyarrhythmias. (2017)
  • 著者名/発表者名: 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.
  • 学会等名: APHRS 2017/JHRS 2017.
  • 国際学会
• [学会発表] Hypertrabeculation at left ventricular apex is highly prevalent and may affect the formation of both J-waves and T-waves in long QT Syndrome. (2017)
  • 著者名/発表者名: Tadashi Nakajima, Yoshiaki Kaneko, Koji Kurosawa, Takashi Iizuka, Shuntaro Tamura, Tommy Dharmawan, Tadanobu Irie, Masahiko Kurabayashi.
  • 学会等名: APHRS 2017/JHRS 2017.
  • 国際学会
• [学会発表] Inherited primary arrhythmia syndrome presenting with phenotypic features of catecholaminergic polymorphic ventricular tachycardia plus prominent U-waves. (2017)
  • 著者名/発表者名: Tommy Dharmawan, Tadashi Nakajima, Seiko Ohno, Takashi Iizuka, Tadanobu Irie, Yoshiaki Kaneko, Minoru Horie, Masahiko Kurabayashi.
  • 学会等名: APHRS 2017/JHRS 2017.
  • 国際学会
• [学会発表] The clinical and genetic predispositions to ventricular tachyarrhythmias associated with vasospastic angina. (2017)
  • 著者名/発表者名: 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.
  • 学会等名: ESC Congress 2017.
  • 国際学会