Elucidation of molecular pathogenesis of ITPA deficiency and development of its treatment

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06960
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kyushu University
• Principal Investigator: Tsuchimoto Daisuke 九州大学, 生体防御医学研究所, 助教 (70363348)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: てんかん / イノシン三リン酸分解酵素 / 脱分極

Outline of Final Research Achievements

To clarify a molecular mechanism of epileptic encephalopathy caused by ITPA deficiency, we established and analyzed neural stem cell specific Itpa knockout mice (cKO mice). The cKO mice showed spontaneous and audiogenic epilepsy. Patch clamp analysis revealed depolarization of resting membrane potential of neuronal cells in cKO mouse brains. These cells also exhibited increased frequency of action potential firing, increased frequency and amplitude of miniature excitatory post synapse current, and increased frequency of miniature inhibitory post synapse current. These results are suggesting that depolarization of ITPA-deficient neurons may cause epilepsy. In addition, we established an ITPA-deficient clone of Neuro2a, a mouse neuroblastoma derived cell line for a screening system of medical drug for human ITPA-deficiency.

Free Research Field

神経科学、生化学、分子生物学、核酸代謝、

Academic Significance and Societal Importance of the Research Achievements

早期乳児てんかん性脳症（EIEE）は重篤な先天性疾患であるがその原因遺伝子は多岐にわたる。一部のタイプは神経細胞の興奮性に関わるイオンチャネル関連遺伝子の変異によって引き起こされていることが知られているがメカニズムが不明の原因遺伝子が多い。EIEEの一つEIEE35はITPA遺伝子の変異が原因であることが2015年に報告されたがメカニズムは不明であった。ITPA欠損が神経細胞の静止膜電位脱分極を引き起こし神経細胞の易興奮性とてんかん発作を引き起こすことを明らかにした本研究はITPA欠損症のみならず他のてんかん性脳症のメカニズム解明と治療法確立にも繋がる可能性があり学術的意義と社会的意義が高い。