2020 Fiscal Year Final Research Report
Mechanism of genetic hypouricosuric hyperuricemia
Project/Area Number |
17K09868
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Metabolomics
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Research Institution | Kyorin University |
Principal Investigator |
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Project Period (FY) |
2017-04-01 – 2021-03-31
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Keywords | 尿酸 / 尿酸輸送体 / 遺伝子変異 |
Outline of Final Research Achievements |
Several genome wide association studies have suggested that SLC2A9 gene plays an important role in hyperuricemia/gout. Around 80% of patients with hyperuricemia are reported to have decreased urinary excretion of urate. Because SLC2A9 is a urate reabsorptive transporter, we hypothesized that gain-of-function mutation and/or overexpression of SLC2A9 can explain low urinary excretion of urate in such patients. Genome sequence was obtained from a hyperuricemic patient and his father, who is also hyperuricemic, and his mother, who had normal urate levels. The patient had 2 mutations in SLC2A9 and these mutations did not affect urate transport activity. Two rare variants in the enhancer region of SLC2A9, existing both in the patient’s and his father’s, but not in his mother’s genome showed increased promoter activity in luciferase assay. We knocked in these 2 variants into HepG2 cells by CRISPR-Cas9 but the cells failed to show increased expression of SLC2A9.
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Free Research Field |
薬理学
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Academic Significance and Societal Importance of the Research Achievements |
腎臓での尿酸再吸収の調節に最も重要であると考えられる輸送体SLC2A9の機能や発現の上昇が高尿酸血症の大部分を占める排泄低下型の病態を説明できるのではないかと考えて研究を行ったが、この仮説を直接的に支持する結果は得られなかった。さらに症例をふやして解析していく必要はあるものの、今回の研究からは、この輸送体を高尿酸血症の創薬標的にするモチベーションにはつながらなかった。
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