Identification of molecular mechanism in a novel congenital malformation syndrome caused by retriever dysfunction.

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K23823
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: Nagoya City University (2023); Nagoya University (2019-2022)
• Principal Investigator: Kato Kohji 名古屋市立大学, 医薬学総合研究院(医学), 助教 (40844056)
• Project Period (FY): 2019-08-30 – 2024-03-31
• Keywords: 3C症候群 / エンドソームリサイクル / 脂質異常症 / VPS35L / レトリーバー複合体

Outline of Final Research Achievements

We reported VPS35L as a novel causative gene for Ritcher-Schinzel syndrome (also known as 3C syndrome) and established the disease concept by accumulating cases through international collaborative research. The accumulation of patients revealed a diverse range of complications. Therefore, we established VPS35L-deficient cells to investigate the molecular mechanisms of patient phenotypes, and particularly elucidated that changes in the expression of LRP1 and LDLR are responsible for lipid abnormalities. Additionally, to examine various phenotypes observed in patients at the individual level, we established VPS35L-deficient mice for the first time in the world and demonstrated that it is embryonic lethal. Furthermore, we generated organ-specific knockout mice and established analysis systems for each tissue.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

本研究成果の学術的意義としては、新規の疾患概念を確立したことにあります。これにより、従来原因が不明であった先天異常症候群の患者さんの診断が可能となり、同一の診断を有する患者さんを集積していくことで、疾患の理解を深め、定期的なフォローアップに役立てることが可能です。また、その疾患の病態を解明し、将来的な治療法や介入方法を検討していくことで、患者さんに対してより良い医療を提供できる可能性があります。