Elucidation of the pathological mechanism of neuronal cell death induced by abnormal T-type calcium channel

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17014
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Yokohama City University
• Principal Investigator: KUNII Misako 横浜市立大学, 医学部, 助教 (80725200)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: CACNA1G variant / patch-clamp / VGCCs

Outline of Final Research Achievements

We found three patients with de novo heterozygous CACNA1G variants in developmental delay and early-onset epileptic encephalopathies. Two patients were found to have known pathological mutants: p.(Ala961Thr) and p.(Met1531Val). One patient was revealed to harbor a previously unreported heterozygous variant: p.(Ile1273Phe).
Electrophysiological study using HEK293T cells including oscillation analysis demonstrated no significant changes of T-type Ca2+ currents by p.(Ile1273Phe).The clinical phenotype of patient with p.(Ile1273Phe) variant was relatively mild in terms of gross motor function, as she can walk alone at the time of writing. The effects of p.(Ile1273Phe) variant on channel function and clinical symptoms may be smaller than those of p.(Ala961Thr) and p.(Met1531Val), which accounts for the normal results shown in the current electrophysiological experiments.The pathogenicity of the p.(Ile1273Phe) variant remains unresolved.

Free Research Field

神経内科学

Academic Significance and Societal Importance of the Research Achievements

我々は新規変異の可能性があるIle1273Pheをもつ症例について臨床症状，検査所見などを含め詳細に報告した．培養細胞を用いた電気生理学的検討ではIle1273Phe変異によるCa電流の異常は今回検出できなかったが，臨床症状が他の変異より軽いことを反映しているものと考えた．CACNA1G変異は，これまでに報告されている良性のてんかんや脊髄小脳変性症，小児発症の小脳萎縮症のみならず，West症候群，Rett症候群様発達障害等の幅広い疾患スペクトラムを形成している可能性を示した．これによりチャネルの変異によっておこる疾患，いわゆるチャネオパチーという疾患概念の理解がさらに進展するものと考えられる．