Identification of novel disease genes and analysis of their molecular functions in progressive familial intrahepatic cholestasis

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K16240
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: University of Tsukuba
• Principal Investigator: Imagawa Kazuo 筑波大学, 医学医療系, 講師 (40708509)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 胆汁うっ滞 / 遺伝性肝疾患 / エクソーム

Outline of Final Research Achievements

In this study, we conducted a comprehensive genetic analysis using a next-generation sequencer for neonatal-onset bile stasis of unknown aetiology, and found cases that were difficult to diagnose by analysis of known disease-related genes. We obtained basic data for further analysis using comprehensive exploratory methods such as exome analysis, transcriptome analysis using liver tissue, and methylome analysis. In addition, we performed molecular functional analysis of gene mutations found in a case of progressive familial intrahepatic cholestasis to evaluate the pathogenesis in vitro and to evaluate the efficacy of small molecules.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

新生児乳児期発症の原因不明胆汁うっ滞症の中には未だ疾患と関連する遺伝子異常が同定されず、今後新規疾患概念の確立に寄与できる集団が含まれていることが明らかになった。今後の胆汁うっ滞病態の分子機序を考察するうえで重要な基礎データが得られた。今後は未診断患者の一群から新規疾患の発見が期待できる。また、日本で最も多く検出されたABCB11変異について、分子機能解析を実施し、病態と新規薬剤の薬効評価を行い、将来の分子機序を基礎とした治療応用への展開も期待される結果が得られた。