Influence of neonatal variants in cardiac Na channel mutations causing severe arrhythmias
| Project/Area Number |
18K07858
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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 | Tokyo Women's Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
羽山 恵美子 東京女子医科大学, 医学部, 非常勤講師 (00349698)
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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 |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | SCN5A / LQT3 / 疾患iPS細胞 / 心筋細胞 / イオンチャネル / QT延長症候群 |
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| Outline of Final Research Achievements |
Study of neonatal Nav1.5 variant with a gain-of-function type mutation R1623Q associated with severe fetal/neonatal arrhythmia was conducted by automated patch-clamp technique using stable expression cell lines of the variants with or without the mutations. The R1623Q mutation slowed decay of the Na current (INa) markedly and increased the late INa. The neonatal variant decreased peak INa. Neonatal variant with R1623Q mutation also decreased the peak INa, slowed the decay, and increased the late INa. These results suggested that the neonatal variant with R1623Q mutation might associate with severe arrythmia by augmentation of the late INa in the intrinsically low INa in the fetal/neonatal period.
We generated iPS cell lines from two patients with the R1623Q mutation, and differentiated into cardiomyocytes. Functional analyses showed that the iPS cells derived cardiomyocytes prolonged FPD (QT) and HERG inhibitor E4031 induced arrythmia like changes in the field potential recordings.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の学術的意義は、① 遺伝子変異を導入したNav1.5チャネル恒常発現株の樹立法、さらにオートパッチクランプを用いた電気生理学的機能評価系を作製できたこと、② 不死化B細胞ライブラリーから疾患iPS細胞を作製、心筋分化、機能解析の道筋を開拓できたことである。
本研究の社会的意義は、本研究で構築した先天性心Naチャネル疾患のモデル実験系を用いて重篤な先天性チャネル疾患の機能情報を蒐集し、治療経験と合わせることができれば、患者予後の推測、治療薬剤の選択などに役立てられることである。
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Report
(4 results)
Research Products
(1 results)
