mRNA-Seq analysis in KCNQ2-related epilepsy model mice and the exploration of novel therapeutic drug candidates for KCNQ2-EE

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17347
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Fukuoka University
• Principal Investigator: Shibata Mami 福岡大学, 医学部, 助教 (20816392)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: KCNQ2 / てんかん / RNA-Seq / トランスクリプトーム

Outline of Final Research Achievements

KCNQ2 gene encodes potassium channel subunits Kv7.2, which form heterotetrameric Kv7.2/Kv7.3 channel with Kv7.3 (encoded by KCNQ3 gene). Kv7.2/Kv7.3 channels are highly expressed in the brain, are enriched at the axonal initial segment, suppressing neuronal excitability. Mutations in KCNQ2 gene commonly cause two types of epilepsy: Self-limited Benign Familial Neonatal Epilepsy (SFNE) and Epileptic Encephalopathy (EE), with the haplo-insufficient and dominant-negative effects on Kv7.2/Kv7.3 channels, respectively. However, in this study, we uncovered that transcriptional patterns of hippocampus were different between SFNE and KCNQ2-EE in model mice, especially of the expression levels of Kcnq2 were less in KCNQ2-EE mice compared with those in control litters, through all postnatal ages. These findings would provide insight into the development of novel therapeutics for KCNQ2-related epilepsy.

Free Research Field

バイオインフォマティクス

Academic Significance and Societal Importance of the Research Achievements

同一遺伝子の変異に起因するSFNEとKCNQ2-EEの重症度の違いは、Kv7.2/Kv7.3チャネルの機能不全レベルに依存すると考えられてきた。本研究では、SFNE、KCNQ2-EE患者の遺伝子変異を保有するモデルマウスを用い、SFNEとKCNQ2-EEの分子病態はmRNAレベルで異なることを明らかにした。この成果はKCNQ2-EEに対する治療薬開発において、核酸治療薬という全く新規の可能性を示すものである。また、本研究ではSFNE、KCNQ2-EEモデルマウスのてんかんに関する表現形、その重症度の違いを明らかにしたことから、これらモデルマウスのKCNQ2-EE創薬開発への有用性を確立した。