Identification of a novel drug target for rare disease using murine model of cystinosis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07149
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Okamura Tadashi 国立研究開発法人国立国際医療研究センター, その他部局等, 実験動物管理室長 (00333790)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 希少疾患 / マウス / シスチノーシス / 相関解析 / シスチン

Outline of Final Research Achievements

Cystinosis is a rare progressive lysosomal storage disorder characterized by the accumulation of cystine in lysosomes, which is caused by a defect of cystine transporter called cystinosin (CTNS). It has been reported that renal dysfunction in Ctns deficient mice was dependent on their genetic background. The renal cystine levels of C57BL/6 Ctns deficient mice were much higher than those of FVB/N and the mixed 129Sv Ctns deficient mice. To clarify the genetic basis of cystine accumulation, we performed genetic association study using backcross progeny. A recessively acting locus responsible for the marked cystine accumulation (cysa) was mapped on mouse chromosome 12. The sequence analyses on the C57BL/6 and FVB/N genome detected a C57BL/6 specific variant leading stop gain within the cysa locus; the variant in Ahr was predicted to disrupt the protein function. Thus, Ahr is a potential candidate gene for the cysa locus. This will be the focus of future studies in both mice and humans.

Free Research Field

実験動物学

Academic Significance and Societal Importance of the Research Achievements

希少疾患はこれまで、発症頻度の低さから数少ない患者を救済する慈善医療で、収益性がないと考えられていた。しかし、希少疾患研究から新たな分子創薬標的が発見され、「頻度が高い病気」（common disease）に対する新薬開発への手がかりを提供することがいくつかの疾患で示されている。本研究により、細胞内のシスチン蓄積とダイオキシンの受容体である芳香族炭化水素受容体遺伝子との関連が示唆され、新たな創薬標的となり得る可能性が示された。