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Type XV OI is a moderate to severe form of skeletal dysplasia caused by WNT1 variants. In this cohort study from southern China, we summarized the clinical phenotypes of patients with WNT1 variants and found that the proportion of type XV patients was around 10.3% (25 out of 243) with a diverse spectrum of phenotypes. Functional assays indicated that variants of WNT1 significantly impaired its secretion and effective activity, leading to moderate to severe clinical manifestations, porous bone structure, and enhanced osteoclastic activities. Analysis of proteomic data from human skeleton indicated that the expression of SOST (sclerostin) was dramatically reduced in type XV patients compared to patients with COL1A1 quantitative variants. Single-cell transcriptome data generated from human tibia samples of patients diagnosed with type XV OI and leg-length discrepancy, respectively, revealed aberrant differentiation trajectories of skeletal progenitors and impaired maturation of osteocytes with loss of WNT1, resulting in excessive CXCL12+ progenitors, fewer mature osteocytes, and the existence of abnormal cell populations with adipogenic characteristics. The integration of multi-omics data from human skeleton delineates how WNT1 regulates the differentiation and maturation of skeletal progenitors, which will provide a new direction for the treatment strategy of type XV OI and relative low bone mass diseases such as early onset osteoporosis.<\/jats:p>","DOI":"10.1093\/jbmr\/zjae123","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T07:49:37Z","timestamp":1723189777000},"page":"1253-1267","source":"Crossref","is-referenced-by-count":13,"title":["Multi-omics analyses reveal aberrant differentiation trajectory with WNT1 loss-of-function in type XV osteogenesis imperfecta"],"prefix":"10.1093","volume":"39","author":[{"given":"Zhijia","family":"Tan","sequence":"first","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"},{"name":"The University of Hong Kong Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, , Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peikai","family":"Chen","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"},{"name":"The University of Hong Kong School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, , Hong Kong, China"},{"name":"The University of Hong Kong-Shenzhen Hospital The AI and Big Data Lab, , Shenzhen, 518053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The University of Hong Kong Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, , Hong Kong, China"},{"name":"The Chinese University of Hong Kong School of Biomedical Sciences, Faculty of Medicine, , Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiu Tung","family":"Shek","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeluan","family":"Li","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlin","family":"Zhou","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yapeng","family":"Zhou","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shijie","family":"Yin","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Dong","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Feng","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janus Siu Him","family":"Wong","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"},{"name":"The University of Hong Kong Department of Orthopaedics and Traumatology, Li Ka Shing Faculty of Medicine, , Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Gao","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital Department of Orthopaedics and Traumatology, , Shenzhen, 518053, China"},{"name":"Clinical Research Center for Rare Diseases, The University of Hong Kong-Shenzhen Hospital , Shenzhen, 518083, China"},{"name":"The Chinese University of Hong Kong School of Biomedical Sciences, Faculty of Medicine, , Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Kai Tsun","family":"To","sequence":"additional","affiliation":[{"name":"The University of Hong Kong-Shenzhen Hospital 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