2022 Fiscal Year Final Research Report
Pathogenesis of phenotypic heterogeneity in MAP3K7 related disorders
| Project/Area Number |
20K09916
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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 57020:Oral pathobiological science-related
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| Research Institution | National Center for Child Health and Development |
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Principal Investigator |
Yanagi Kumiko 国立研究開発法人国立成育医療研究センター, ゲノム医療研究部, 研究員 (90294701)
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| Co-Investigator(Kenkyū-buntansha) |
要 匡 国立研究開発法人国立成育医療研究センター, ゲノム医療研究部, 部長 (40264288)
石谷 太 大阪大学, 微生物病研究所, 教授 (40448428)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 心脊椎手根骨顔症候群 / 前頭・骨幹端異形成症 / MAP3K7 / 単一遺伝性疾患 / 表現型異質性 / 網羅的遺伝学的解析 |
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| Outline of Final Research Achievements |
MAP3K7 is known as a causative gene for cardiospinocarpal facies syndrome (CSCF) which is characterized by cardiac abnormalities, carpal fusion, and dysmorphic facial appearance. In this study, we identified a novel pathogenic variant of MAP3K7 （p.Ser192Gly）and analysed its function.
In silico analysis predicted that the variant would result in the loss of the phosphorylation site, and attenuation of its autophosphorylation was confirmed by in vitro analysis. In zebrafish in which MAP3K7 was selectively suppressed with MAP3K7 inhibitors or morpholino, the number of individuals with a CSCF-like phenotype was significantly increased. Peripheral blood cells obtained from the CSCF patient had reduced cell adhesion to MAP3K7 stimulation. We also identified a novel frameshift variant in TAB2 which formed a complex with MAP3K7 in patients with CSCF-like phenotype. These results suggested that loss of function of the MAP3K7 pathway might be involved in the CSCF-like phenotype.
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| Free Research Field |
分子遺伝学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、心室中隔欠損、手根骨癒合、特異的な顔貌、歯の放出遅延などのCSCFの表現型発現にMAP3K7の機能喪失型バリアントが関与していることがin vitroやin vivoでの解析を通じて明確に示すことができた。加えて、CSCF様の表現型を呈する別の症例でMAP3K7と複合体を形成するTAB2に新規のフレームシフトバリアントを同定されたことは、MAP3K7を中心とする機能喪失型のシグナルカスケードがCSCF類似の表現型に関与することを示唆しており、あらたな疾患概念の提唱につながる可能性が高く、学術的にも意義のある発見となった。
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