Elucidation of pathogenesis and clinical characteristics, establishment of the therapy in patients with LQTS caused by calcium related gene variants
| Project/Area Number |
18K07875
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
Ohno Seiko 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 先天性QT延長症候群 / カルシウムチャネル / カルモジュリン / CACNA1C / CALM1 / CALM2 / CACNA1c / Calmodulin / RYR2 / LQTS / LQT8 / LQT15 / カルシウムイオンチャネル / リアノジン |
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| Outline of Final Research Achievements |
Congenital long QT syndrome (LQTS) is mainly caused by mutations in genes encoding potassium and sodium channels. Along with the advances in the genetic analysis, LQTS caused by mutations in genes encoding other types of ion channels have been frequently reported. Therefore, we performed analysis targeting for the genes encoding calcium related ion channels and proteins.
Mutations in CACNA1C encoding L-type calcium channel are the cause for LQTS type 8, and the prevalence of it among LQTS patients has proved to be higher than it reported. Now we are conducting the functional analysis of the mutant L-type calcium channel. CALM1-3 encode calmodulin which works for the binding between calcium ion and proteins. We identified several mutations in CALM1-3 in LQTS patients. Their mutations are all de novo, and the phenotypes of them were very severe. RYR2 is a gene encoding cardiac ryanodine channel (RyR2), and we elucidated that loss-of-function type RyR2 caused LQTS.
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| Academic Significance and Societal Importance of the Research Achievements |
先天性QT延長症候群（LQTS）は突然死を来す遺伝性疾患である。原因遺伝子は報告されているものの、変異が同定されない場合があり、カルシウムイオン（Ca2+）関連遺伝子の変異が考えられた。そこで次世代シークエンサーを用いてLQTS患者の遺伝子を解析したところ、カルシウムチャネルをコードするCACNA1C、様々なタンパクとCa2+との結合に関わるカルモジュリンをコードする遺伝子、および細胞内Ca2+をコントロールするリアノジンチャネルをコードするRYR2に変異を同定した。これらの遺伝子変異の解析を実施することによって、これまで報告の少ないCa2+関連のLQTSについて明らかにすることができた。
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Report
(4 results)
Research Products
(77 results)
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[Journal Article] Impact of Medical Castration on Malignant Arrhythmias in Patients With Prostate Cancer.2021
Author(s)
Hasegawa K, Ito H, Kaseno K, Miyazaki S, Shiomi Y, Tama N, Ikeda H, Ishida K, Uzui H, Ohno S, Horie M, Yokoyama O, Tada H.
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Journal Title
J Am Heart Assoc.
Volume: 10
Issue: 5
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a <i>Ryanodine Receptor Type 2</i> Missense Mutation2020
Author(s)
Nozaki Y, Kato Y, Uike K, Yamamura K, Kikuchi M, Yasuda M, Ohno S, Horie M, Murayama T, Kurebayashi N, Horigome H
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Journal Title
Circulation Journal
Volume: 84
Issue: 2
Pages: 226-234
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2020-01-24
Related Report
Peer Reviewed / Open Access
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[Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome.2020
Author(s)
Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
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Journal Title
FASEB Journal
Volume: 34
Issue: 5
Pages: 6399-6417
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019
Author(s)
Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
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Journal Title
Circulation
Volume: In press
Issue: 18
Pages: 2157-2169
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Clinical Manifestations and Long-Term Mortality in <i>Lamin A/C</i> Mutation Carriers From a Japanese Multicenter Registry2018
Author(s)
14.Nakajima K, Aiba T, Makiyama T, Nishiuchi S, Ohno S, Kato K, Yamamoto Y, Doi T, Shizuta S, Onoue K, Yagihara N, Ishikawa T, Watanabe I, Kawakami H, Oginosawa Y, Murakoshi N, Nogami A, Aonuma K, Saito Y, Kimura T, Yasuda S, Makita N, Shimizu W, Horie M, Kusano K.
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Journal Title
Circulation Journal
Volume: 82
Issue: 11
Pages: 2707-2714
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2018-10-25
Related Report
Peer Reviewed / Open Access
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[Journal Article] Novel roles of Drosophila FUS and Aub responsible for piRNA biogenesis in neuronal disorders.2018
Author(s)
Wakisaka KT, Tanaka R, Hirashima T, Muraoka Y, Azuma Y, Yoshida H, Tokuda T, Asada S, Suda K, Ichiyanagi K, Ohno S, Itoh M, Yamaguchi M.
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Journal Title
Brain Res.
Volume: 18
Pages: 30646-30652
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Population pharmacokinetics and pharmacogenomics of apixaban in Japanese adult patients with atrial fibrillation.2018
Author(s)
Ueshima S, Hira D, Kimura Y, Fujii R, Tomitsuka C, Yamane T, Tabuchi Y, Ozawa T, Itoh H, Ohno S, Horie M, Terada T, Katsura T.
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Journal Title
Br. J. Clin. Pharmacol.
Volume: -
Issue: 6
Pages: 1301-1312
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Mutation specific clinical characteristics in long QT syndrome type 8; severe phenotype in Timothy syndrome patients.2019
Author(s)
Ohno S, Yoshinaga M, Ozawa J, Fukuyama M, Sato S, Kashiwa A, Yasuda K, Kaneko S, Nakau K, Inukai S, Makiyama T, Aiba T, Suzuki H, Horie M.
Organizer
European Society of Cardiology
Related Report
Int'l Joint Research
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