2020 Fiscal Year Final Research Report
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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| Keywords | 先天性QT延長症候群 |
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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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| Free Research Field |
循環器病学
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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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