| Project/Area Number |
19K17865
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
UCHIYAMA Yuri 横浜市立大学, 附属病院, 助教 (50829794)
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| Project Period (FY) |
2019-04-01 – 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 先天性造血器障害 / 汎血球減少症 / 血小板減少症 / 全エクソーム解析 / 先天性造血障害 / 造血機能不全 |
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| Outline of Research at the Start |
小児期、あるいは若年発症の造血異常や止血凝固異常症に対し、全エクソーム解析を用いた網羅的な遺伝子解析を行うことで、効率的に疾患の遺伝学的な解明を目指す。本手法を用いて既に検出した候補遺伝子に対し、その機能を明らかにし、疾患の遺伝学的な原因を明らかにすることを目指す。これらを明らかにすることで、造血不全や機能異常における、診断率の向上や治療方針決定への大きな寄与へとつながることが予測される。
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| Outline of Final Research Achievements |
Thrombocytopenia occurring in childhood must be differentiated from immune thrombocytopenia, hematological malignancy, bone marrow failure, and inherited thrombocytopenia.
In this study, exome sequencing identified gene A and B in two families with pancytopenia and congenital thrombocytopenia, respectively. The pathogenicity of these two genes and variants were subsequently evaluated by deep-sequencing, RT-PCR, and/or RNA-sequencing. Deep-sequencing results was strongly convinced that this variant was derived from the early-phase somatic mosaicism. However, lymphoblastoid cell lines derived from patient’s blood could not include the cells with the variant. The strong toxicity of the variant of gene A induced cell mortality. A total of 42 families of congenital abnormalities of thrombosis and/or hemostasis was performed for exome sequencing. The diagnostic rate was 23.8% (10/42). Exome sequencing is useful technique for the rare disorder associated with congenital thrombocytopenia.
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| Academic Significance and Societal Importance of the Research Achievements |
先天性血小板減少症の遺伝的原因を明らかにすることで、疾患の背景を明らかにすることができる。造血の過程のどの段階での異常かを同定することは、先天性造血障害における治療方針を検討する上で大きな指針の一つとなるため、新規疾患の遺伝的原因の解明は非常に重要である。これら先天性疾患の遺伝的疾患原因解明は、後天性疾患である多くの造血不全・造血器腫瘍の理解・治療につながることが期待される。
患者抽出方法を含め、本手法を用いた先天性血小板減少症・止血凝固異常症の遺伝的疾患病態の解明は、非常に効率的であることが示された。
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