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Knockdown of<jats:italic>orcl1<\/jats:italic>and overexpression of the<jats:italic>orcl1<\/jats:italic>mutant were performed in HK-2 and MPC5 cells to study its function, while flow cytometry measured reactive oxygen species (ROS), phosphatidylserine levels, and cell apoptosis. Scanning electron microscopy observed crystal adhesion, while transmission electron microscopy examined kidney tissue pathology. Laser scanning confocal microscopy was used to examine endocytosis, and immunohistochemical and immunofluorescence assays detected protein expression. Additionally, podocyte-specific<jats:italic>orcl1<\/jats:italic>knockout mice were generated to investigate the role of<jats:italic>orcl1<\/jats:italic>in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified a mutation resulting in the replacement of Histidine with Arginine at position 318 (R318H) in<jats:italic>ocrl1<\/jats:italic>in the proband.<jats:italic>orcl1<\/jats:italic>was widely expressed in the kidney. In vitro experiments showed that knockdown of<jats:italic>orcl1<\/jats:italic>and overexpression of<jats:italic>ocrl1<\/jats:italic>mutant increased ROS, phosphatidylserine exocytosis, crystal adhesion, and cell apoptosis in HK-2 cells. Knockdown of<jats:italic>orcl1<\/jats:italic>in podocytes reduced endocytosis and disrupted the cell cycle while increasing cell migration. In vivo studies in mice showed that conditional deletion of<jats:italic>orcl1<\/jats:italic>in podocytes caused glomerular dysfunction, including proteinuria and fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study identified an R318H mutation in<jats:italic>orcl1<\/jats:italic>in a patient with Dent-2 Disease. This mutation may contribute to renal injury by promoting ROS production and inducing cell apoptosis in tubular cells, while disrupting endocytosis and the cell cycle, and promoting cell migration of podocytes.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12964-023-01272-4","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T00:02:11Z","timestamp":1701734531000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A missense mutant of ocrl1 promotes apoptosis of tubular epithelial cells and disrupts endocytosis and the cell cycle of podocytes in Dent-2 Disease"],"prefix":"10.1186","volume":"21","author":[{"given":"Limin","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhong","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,5]]},"reference":[{"key":"1272_CR1","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1007\/s00467-016-3499-x","volume":"32","author":"Y van Berkel","year":"2017","unstructured":"van Berkel Y, Ludwig M, van Wijk JAE, Bokenkamp A. 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