2021 Fiscal Year Final Research Report
Genomic analysis of steroid-sensitive nephrotic syndrome using sibling cases
| Project/Area Number |
19H03612
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Tohoku University |
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Principal Investigator |
KURE Shigeo 東北大学, 医学系研究科, 客員教授 (10205221)
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| Co-Investigator(Kenkyū-buntansha) |
菊池 敦生 東北大学, 大学病院, 助教 (30447156)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | ネフローゼ症候群 / ステロイド感受性 / ゲノム解析 / 同胞発症家系 |
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| Outline of Final Research Achievements |
To clarify gene for steroid-sensitive nephrotic syndrom (SSNS) we performed the whole exsome-sequencing of SSNS family with affected sibs, and identified first gene ISTN1, and identified additional 23 mutations in the ISTN1-related genes.To explore a novel SSNS gene we screened additional 7 families with affected sibs and found a compound-heterozygous mutations in IL1RAP gene. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we tested the its functional effect. When stimulated with IL-1β, peripheral blood cells from the patients produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit had impaired binding ability and low reactivity to IL-1β. To confirm the causality of the mutations in a mouse model we analyzed urine protein levels in the Il1rap knockout mouse. However, the protein level was not different form wild-type mouse, suggesting necessity of further analysis.
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| Free Research Field |
小児科学、ゲノム医療
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| Academic Significance and Societal Importance of the Research Achievements |
ネフローゼ症候群には、ステロイド治療が効くステロイド感受性と効かない病型がある。小児では、ステロイド感受性の症例が多数を占めるが、遺伝的背景はステロイド日感受性に比べて解明されていない。本研究では、同胞発症のステロイド感受性症例に着目し、その遺伝的背景を明らかにするゲノム解析を行った。この同様な戦略により、申請者らはこれまで6つの病因となる遺伝子を明らかにしてきた。今回、同様の手法によりIL1RAPという遺伝子に候補遺伝子変異を見出し、その性質を培養細胞内および遺伝子改変マウスを用いて検証したところ、相棒レベルでは機能低下を認めたが、マウスレベルでは認めなかった。現在更なる検証を進めている。
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