{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:29:08Z","timestamp":1790720948088,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T00:00:00Z","timestamp":1694476800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172496"],"award-info":[{"award-number":["82172496"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005046","name":"Natural Science Foundation of Heilongjiang Province","doi-asserted-by":"publisher","award":["H2017030"],"award-info":[{"award-number":["H2017030"]}],"id":[{"id":"10.13039\/501100005046","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Family with sequence similarity 20\u2010member C (FAM20C) is a kinase specific to most of the secreted phosphoproteome. <jats:italic>FAM20C<\/jats:italic> has been identified as the causative gene of Raine syndrome, initially characterized by lethal osteosclerosis bone dysplasia. However, since the identification of the cases of nonlethal Raine syndrome characterized by hypophosphatemia rickets, the previous definition of Raine syndrome has become debatable and raised a question about the role of mutations of <jats:italic>FAM20C<\/jats:italic> in controversial skeletal manifestation in the two forms of the disease. In this study, we aimed to investigate the influence of <jats:italic>FAM20C<\/jats:italic> mutations on skeletogenesis. We developed transgenic mice expressing <jats:italic>Fam20c<\/jats:italic> mutations mimicking those associated with human lethal and nonlethal Raine syndrome. The results revealed that transgenic mice expressing the mutant <jats:italic>Fam20c<\/jats:italic> found in the lethal (<jats:italic>KO;G374R<\/jats:italic>) and nonlethal (<jats:italic>KO;D446N<\/jats:italic>) Raine syndrome exhibited osteomalacia without osteosclerotic features. Additionally, both mutants significantly increased the expression of the <jats:italic>Fgf23<\/jats:italic>, indicating that <jats:italic>Fam20c<\/jats:italic> deficiency in skeletal compartments causes hypophosphatemia rickets. Furthermore, as FAM20C kinase activity catalyzes the phosphorylation of secreted proteomes other than those in the skeletal system, global <jats:italic>FAM20C<\/jats:italic> deficiency may trigger alterations in other systems resulting in osteosclerosis secondary to hypophosphatemia rickets. Together, the findings of this study suggest that <jats:italic>FAM20C<\/jats:italic> deficiency primarily causes hypophosphatemia rickets or osteomalacia; however, the heterogeneous skeletal manifestation in Raine syndrome was not determined solely by specific mutations of <jats:italic>FAM20C<\/jats:italic>. The findings also implicated that rickets or osteomalacia caused by <jats:italic>FAM20C<\/jats:italic> deficiency would deteriorate into osteosclerosis by the defects from other systems or environmental impacts.<\/jats:p>","DOI":"10.1002\/jcp.31105","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T08:59:04Z","timestamp":1694509144000},"page":"2556-2569","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mutations of family with sequence similarity 20\u2010member C gene causing lethal and nonlethal Raine syndrome causes hypophosphatemia rickets"],"prefix":"10.1002","volume":"238","author":[{"given":"Peihong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Stomatology The First Affiliated Hospital of Harbin Medical University Harbin China"},{"name":"Laboratory of Longjiang Scholar, The First Affifiliated Hospital of Harbin Medical University Harbin 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