2018 Fiscal Year Annual Research Report
Novel molecular basis underlying lethal arrhythmic syndrome due to mutations in cardiac Na/Ca exchanger gene
| Project/Area Number |
18H02808
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
蒔田 直昌 国立研究開発法人国立循環器病研究センター, 研究所, 副所長 (00312356)
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| Co-Investigator(Kenkyū-buntansha) |
牧山 武 京都大学, 医学研究科, 助教 (30528302)
渡邊 泰秀 浜松医科大学, 医学部, 教授 (50305380)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | 致死性不整脈 / Na-Ca交換体 / 早期再分極症候群 / QT短縮症候群 / ゲノム編集 / ノックインマウス / パッチクランプ / コンピュータシミュレーション |
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| Outline of Annual Research Achievements |
本研究は、これまで主として心筋イオンチャネルを中心とした研究が進んでいた致死性不整脈の新たな病因として、心筋イオン輸送体に焦点を当てる。申請者はフランスとの共同研究で、致死性不整脈から蘇生された183例に網羅的遺伝子解析をおこなったところ、心電図J波とQT時間短縮を特徴とする20家系に心筋Na-Ca交換体(NCX1)の遺伝子変 異を14個(ミスセンス11種、1塩基欠損による蛋白欠失変異1種、スプライシング部位の変異2種)同定した。パッチクランプで解析した変異NCX1の多くはNa -Ca交換特性が低下し、45Ca取り込み能の低下と細胞膜へのトラフィッキング異常が確認された。ヒト心室筋細胞のコンピュータシミュレーションモデルではNCX1電流の低下によって活動電位の短縮が確認された。Crispr/Cas9法によるゲ ノム編集でNCX1変異L218HのノックインマウスのF1を2系統作成した。繁殖後心電図記録、単離心筋細胞の活動電位記録、薬物負荷試験などを計画していたが、研究代表者が2019年4月から異動すること、移動先が全館移転のため8月まで動物実験ができないことなどから、マウスは2019年夏まで凍結胚として保存することにした。
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| Current Status of Research Progress |
Current Status of Research Progress
3: Progress in research has been slightly delayed.
Reason
研究代表者が2019年4月に異動することになった。移動先の国立循環器病研究センターは5月に全館移転し8月まで動物実験ができない。したがってノックインマウスは2019年夏まで凍結胚として保存することにしたため、動物実験の研究が遅れた。その他の研究はおおむね順調に進行している。
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| Strategy for Future Research Activity |
2019年4月に異動後、可及的早期に実験を再開する。凍結胚は2019年夏に個体復元し、繁殖後予定していた実験に用いる。
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[Journal Article] Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells2019
Author(s)
Yoshinaga D, Baba S, Makiyama T, Shibata H, Hirata T, Akagi K, Matsuda K, Kohjitani H, Wuriyanghai Y, Umeda K, Yamamoto Y, Conklin BR, Horie M, Takita J, Heike T.
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Journal Title
Stem Cell Reports
Volume: 13
Pages: 394～404
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] A de novo gain-of-function KCND3 mutation in early repolarization syndrome2019
Author(s)
Takayama K, Ohno S, Ding W-G, Ashihara T, Fukumoto D, Wada Y, Makiyama T, Kise H, Hoshiai M, Matsuura H, Horie M.
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Journal Title
Heart Rhythm
Volume: 16
Pages: 1698～1706
DOI
Peer Reviewed
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[Journal Article] HCN4 Gene Polymorphisms Are Associated With Occurrence of Tachycardia-Induced Cardiomyopathy in Patients With Atrial Fibrillation2018
Author(s)
Nakano Y, Ochi H, Sairaku A, Onohara Y, Tokuyama T, Motoda C, Matsumura H, Tomomori S, Amioka M, Hironobe N, Ohkubo Y, Okamura S, Makita N, Yoshida Y, Chayama K, Kihara Y.
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Journal Title
Circulation: Genomic and Precision Medicine
Volume: 11
Pages: -
DOI
Peer Reviewed
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[Journal Article] Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants2018
Author(s)
Gray B, Hasdemir C, Ingles J, Aiba T, Makita N, Probst V, Wilde Arthur AM., Newbury-Ecob R, Sheppard MN, Semsarian C, Sy RW, Behr ER.
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Journal Title
Heart Rhythm
Volume: 15
Pages: 1051～1057
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis2018
Author(s)
Yamashita S, Suzuki T, Iguchi K, Sakamoto T, Tomita K, Yokoo H, Sakai M, Misawa H, Hattori K, Nagata T, Watanabe Y, Matsuda N, Yoshimura N, Hattori Y.
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Journal Title
Naunyn-Schmiedeberg's Archives of Pharmacology
Volume: 391
Pages: 1021～1032
DOI
Peer Reviewed
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[Journal Article] Complex aberrant splicing in the induced pluripotent stem cell?derived cardiomyocytes from a patient with long QT syndrome carrying KCNQ1-A344Aspl mutation2018
Author(s)
Wuriyanghai Y, Makiyama T, Sasaki K, Kamakura T, Yamamoto Y, Hayano M, Harita T, Nishiuchi S, Chen J, Kohjitani H, Hirose S, Yokoi F, Gao J, Chonabayashi K, Watanabe K, Ohno S, Yoshida Y, Kimura T, Horie M.
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Journal Title
Heart Rhythm
Volume: 15
Pages: 1566～1574
DOI
Peer Reviewed
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[Presentation] Single Cell Electrophysiological Analysis of iPS Cell-Derived Cardiomyocytes Generated from Long-QT Syndrome Patients Carrying a CALM2 Mutation Using a Membrane Potential Imaging System2019
Author(s)
Yamamoto Y., Makiyama T., Wuriyanghai Y., Kohjitani H., Hirose S., Gao J., Kashiwa A., Huang H., Ishikawa T., Ohno S., Chonabayashi K., Suda K., Yoshida Y., Horie M., Makita N., Kimura T.
Organizer
第66回日本不整脈心電学会
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[Presentation] Modeling Overlap Syndrome of Long QT and Brugada Syndrome Associated with Induced Pluripotent Stem Cells2019
Author(s)
Kashiwa A., Makiyama T., Kohjitani H., Wuriyanghai Y., Yamamoto Y., Jungshan G., Huang H., Ishikawa T., Ohno S., Toyoda F., Sato S., Horie M., Makita N., Kimura T.
Organizer
The 40th Heart Rhythm Society Scientific Sessions
Int'l Joint Research
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[Presentation] Modeling Overlapping Phenotypes of Long-QT and Brugada Syndrome with CACNA1C-E1115K that Alters Ion Selectivity of the Cardiac L-Type Calcium Channel Using Induced Pluripotent Stem Cells2019
Author(s)
Kashiwa A., Makiyama T., Kohjitani H., Hirose S., Gao J., Kashiwa A., Huang H., Ishikawa T., Ohno S., Chonabayashi K., Suda K., Yoshida Y., Horie M., Makita N., Kimura T.
Organizer
第66回日本不整脈心電学会
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[Presentation] Cardiac Emerinopathy, Novel Nonsyndromic Xlinked Left Ventricular Noncompaction Associated With Progressive Atrial Conduction Disturbance2019
Author(s)
Ishikawa T., Barc J., Mishima H., Hirono K., Terada S., Kowase S., Sato T., Mukai Y., Yui Y., Ohkubo K., Kimoto H., Hata Y., Aiba T., Ohno S., Chishaki A., Shimizu W., Horie M., Ichida F., Nogami A., Yoshiura K., Schott JJ., Makita N.
Organizer
The 40th Heart Rhythm Society Scientific Sessions
Int'l Joint Research
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[Presentation] Genetic Background in Patients with Idiopathic Ventricular Fibrillation: Known Gene Screening from Whole Exome Analysis Data2019
Author(s)
Aiba T., Cha, Pei-Chieng, Takahashi A., Ohno S., Kamakura T., Ishikawa T., Ishibashi-Ueda H., Harada-Shiba M., Minamino N., Hayashi K., Yagihara N., Nakano Y., Itoh H., Miyamoto Y., Tanaka T., Makita N., Horie M., Shimizu W., Kusano K., Yasuda S.
Organizer
第83回日本循環器学会学術集会
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[Presentation] Genetics and Clinical Aspects of Congenital Long-QT Syndrome: Results from the Japanese Multicenter Registry2019
Author(s)
清水渉, 山形研一郎, 野田崇, 草野研吾, 宮崎文, 牧山武, 伊藤英樹, 大野聖子, 渡部裕, 林研至, 森田宏, 吉永正夫, 福田恵一, 宮本恵宏, 鎌倉史郎, 田中敏博, 住友直方, 萩原誠久, 蒔田直昌, 堀江稔, 相庭武司
Organizer
第83回日本循環器学会学術集会
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[Presentation] Structural Insights into Catecholaminergic Polymorphic Ventricular Tachycardia-associated RyR2 Mutant Channels using a Three-dimensional In Silico Model.2019
Author(s)
Gao J., Makiyama T., Ohno S., YamamotoY., Wuriyanghai Y., Kohjitani H., Kashiwa A., Huang H., Katou K., Horie M., Kimura T.
Organizer
European Society of Cardiology Congress 2019
Int'l Joint Research
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[Presentation] Automatic Computational Action Potential Analyzing System Enables Accurate Drug Response Interpretation and Prediction in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes2019
Author(s)
Kohjitani H., Kouda S., Himeno Y., Makiyama T., Kashiwa A., Wuriyanghai Y., Yamamoto Y., Horie M., Kimura T., Noma A., Amano A.
Organizer
The 40th Heart Rhythm Society Scientific Sessions
Int'l Joint Research
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[Presentation] Algorithmic Auto-Recreation System of hiPSC-CMs Simulation and Prediction of Drug Testing2019
Author(s)
Kohjitani H., Kouda S., Himeno Y., Makiyama T., Huang H., Gao J., Kashiwa A., Wuriyanghai Y., Yoshinaga D., Kimura T., Amano A.
Organizer
第83回日本循環器学会学術集会
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[Presentation] Overlapping Sick Sinus Syndrome Associated with SCN5A Mutations in Patients with Brugada Syndrome2019
Author(s)
Kashiwa A., Makiyama T., Ohno S., Aoki H., Kohjitani H., Wuriyanghai Y., Yamamoto Y., Gao J., Hai H., Horie M., Kimura T.
Organizer
第83回日本循環器学会学術集会
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[Presentation] 不整脈症候群で心臓が構造的に正常な患者における心筋症の原因遺伝子変異の特定2018
Author(s)
八木原伸江, 渡部裕, 蒔田直昌, 堀江稔, 清水渉, 大野聖子, 長谷川奏恵, 相庭武司, 田中敏博, 角田達彦, 重水大智, 南野徹
Organizer
第82回日本循環器学会学術集会
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[Presentation] CALM2関連性QT延長症候群iPSCモデルにおいて、l-cis-diltiazemは遅延したL型calciumチャネルの不活性化をさらに強める2018
Author(s)
横井文香, 牧山武, 山本雄大, 張田健志, Yimin Wuriyanghai, 早野護, 西内英, 糀谷泰彦, 廣瀬紗也子, 高景山, 大野聖子, 豊田太, 吉田善紀, 蒔田直昌, 堀江稔, 木村剛
Organizer
第82回日本循環器学会学術集会
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[Presentation] Torsadogenic Action Of Late Na+ Current In Experimental Electrical Storm2018
Author(s)
Yamazaki M., Tsuji Y. , Niwa R., Tomii N., Arafune T., Honjo H., Dobrev D., Nattel S., Kodama I., Sakuma I., Makita N.
Organizer
The 39th Heart Rhythm Society Scientific Sessions
Int'l Joint Research
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[Presentation] Torsadogenic Action Of Late Na+ Current In Experimental Electrical Storm2018
Author(s)
Yamamoto Y., Makiyama T, Wuriyanghai Y., Kohjitani H., Hirose S., Gao J, Kashiwa A., Kimura T., Ishikawa T., Motomura H., Makita N, Ohno S., Chonabayashi K., Yoshida Y., Suda K., Horie M
Organizer
The 11th Asia Pacific Heart Rhythm Society Scientific Session
Int'l Joint Research
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[Presentation] The inactivation of L-type Ca2+ Channel was impaired in Human iPS Cell Model of Long-QT Syndrome with CALM2-D134H Mutation.2018
Author(s)
Yamamoto Y., Makiyama T., Harita T., Hayano M., Nishiuchi S., Wuriyanghai Y., Kohjitani H., Hirose S., Yokoi F., Ishikawa T., Ohno S., Chonabayashi K., Suda K., Yoshida Y., Horie M., Makita N., Kimura T.
Organizer
第82回日本循環器学会学術集会
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[Presentation] Mechanisms of Electrical Storm Associated With QT Prolongation: Successful Mapping of Torsades de Pointes in Rabbits2018
Author(s)
Tsuji Y., Yamazaki M., Niwa R., Tomii N., Arafune T., Honjo H., Dobrev D., Nattel S., Kodama I., Sakuma I., Makita N
Organizer
American Heart Association Annual Scientific Sessions 2018
Int'l Joint Research
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[Presentation] HCN4 Polymorphisms and Tachycardia Induced Cardiomyopathy2018
Author(s)
Nakano Y., Ochi H., Onohara Y., Sairaku A., Tokuyama T., Motoda C., Matsumura H., Tomomori S., Amioka M., Hironobe N., Ohkubo Y., Okamura S., Makita N., Yoshida Y., Chayama K., Kihara Y.
Organizer
The 65th Annual Meeting of the Japan Heart Rhythm Society
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[Presentation] Clinical Manifestations and Long-term Mortality in Lamin A/C Mutation Carriers from the Japanese Multicenter Registry2018
Author(s)
Nakajima K., Aiba T., Makiyama T., Nishiuchi S., Ohno S., Doi T., Shizuta S., Onoue K., Yagihara N., Ishikawa T., Watanabe I., Oginosawa Y., Nogami A., Aonuma K., Saitoh Y., Kimura T., Makita N., Shimizu W., Horie M., Kusano K.
Organizer
The 65th Annual Meeting of the Japan Heart Rhythm Society
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[Presentation] Mutation Hot-spot-based Risk Stratification In Long QT Syndrome Type 1: Data From A Nationwide Japanese LQT Registry2018
Author(s)
Kashiwa A., Aiba T., Makimoto H., Yamagata K. , Keiko S. , Yagihara N., Watanabe H. , Ohno S., Hayashi K. , Sumitomo N., Yoshinaga M. , Morita H., Miyamoto Y. , Makita N. , Horie M., Yasuda S., Kusano K., Shimizu W. , The_Japanese_LQTS_registry_investigators.
Organizer
The 39th Heart Rhythm Society Scientific Sessions
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 Syndrome2018
Author(s)
Ishikawa T., Mishima H., Ohno S., T. Aiba, 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
The 65th Annual Meeting of the Japan Heart Rhythm Society
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[Presentation] Significance of cell-specific precise computer simulation using new mathematical models of human induced pluripotent stem cell derived cardiomyocyte in drug testing2018
Author(s)
Kohjitani H., Kouda S., Himeno Y., Makiyama T., Yokoi F., Hirose S., Wuriyanghai Y., Yamamoto Y., Horie M., Kimura T., Noma A., Amano A.
Organizer
European Society of Cardiology Congress 2018
Int'l Joint Research
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[Presentation] Analysis of Disease-Causing Mechanism of Lamin A/C-Related Cardiomyopathy Using Homozygous Lamin A/C Knock out Human Induced Pluripotent Stem Cell Model2018
Author(s)
Wuriyanghai Y., Makiyama T., Yamamoto Y., Nishiuchi S., Hirose S., Kohjitani H., Gao J., Kashiwa A., Ohno S., Horie M., Kimura T.
Organizer
The 11th Asia Pacific Heart Rhythm Society Scientific Session
Int'l Joint Research
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