{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:52:13Z","timestamp":1787237533366,"version":"build-2736575974"},"reference-count":106,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"Scientific and Technological Research Council of T\u00fcrkiye","doi-asserted-by":"publisher","award":["222S011"],"award-info":[{"award-number":["222S011"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004410","name":"Scientific and Technological Research Council of T\u00fcrkiye","doi-asserted-by":"publisher","award":["ABAPKO THD-2024-2170"],"award-info":[{"award-number":["ABAPKO THD-2024-2170"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Acibadem Mehmet Ali Aydinlar University","award":["222S011"],"award-info":[{"award-number":["222S011"]}]},{"name":"Acibadem Mehmet Ali Aydinlar University","award":["ABAPKO THD-2024-2170"],"award-info":[{"award-number":["ABAPKO THD-2024-2170"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive cartilage disorder caused by biallelic variants in CCN6, which encodes the matricellular protein WISP3. Although WISP3 is thought to contribute to extracellular matrix (ECM) homeostasis, its precise molecular role in PPD remains unclear. To elucidate how disease-associated CCN6 variants affect chondrocyte function, we overexpressed four variants\u2014p.Cys52*, p.Tyr109*, p.Gly83Glu, and p.Cys114Trp\u2014all located within the IGFBP domain, and evaluated their impact on parameters including redox balance, ER stress, ECM remodeling, gene expression, and protein\u2013protein interactions. The p.Cys52* variant resulted in rapid degradation of WISP3, indicating a complete loss-of-function. The p.Tyr109* variant disrupted ECM regulation, markedly reducing protein interaction capacity, which was correlated with elevated mitochondrial ROS (mtROS) levels and triggered a strong response that led to programmed cell death. Although both missense variants yielded full-length proteins, their effects diverged significantly: p.Gly83Glu induced minor cellular alterations, whereas p.Cys114Trp caused severe protein destabilization, increased ROS accumulation, and high levels of ER stress. Proteomic analysis revealed that p.Cys114Trp acquired novel interaction partners, suggesting a potential gain-of-function mechanism. Collectively, these findings demonstrate that the functional consequences of CCN6 variants depend not only on variant type or domain location but also on their positional and structural context. The distinct cellular responses elicited by each variant underscore the importance of functional validation in modeling PPD pathogenesis and offer valuable biological and therapeutic perspectives.<\/jats:p>","DOI":"10.3390\/ijms26188838","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T07:51:46Z","timestamp":1757577106000},"page":"8838","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Molecular Consequences of CCN6 Variants Encoding WISP3 in Progressive Pseudorheumatoid Dysplasia"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0796-5502","authenticated-orcid":false,"given":"Gulipek","family":"Guven Tasbicen","sequence":"first","affiliation":[{"name":"Department of Medical Biotechnology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"},{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3416-8586","authenticated-orcid":false,"given":"Ali","family":"Tufan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Batuhan","family":"Savsar","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5359-4357","authenticated-orcid":false,"given":"Alper","family":"Bulbul","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Bioinformatics, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3448-4395","authenticated-orcid":false,"given":"Zeynep","family":"Tonbul","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4864-7403","authenticated-orcid":false,"given":"Elif","family":"Guzel","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0497-3294","authenticated-orcid":false,"given":"Dilay Hazal","family":"Ayhan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9483-3593","authenticated-orcid":false,"given":"Ahmet Can","family":"Timucin","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"},{"name":"Department of Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4360-9310","authenticated-orcid":false,"given":"Umut Inci","family":"Onat","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"},{"name":"Department of Molecular Biology and Genetics, Institute of Natural and Applied Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunseli","family":"Bayram Akcapinar","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8310-4053","authenticated-orcid":false,"given":"Ozlem","family":"Akgun Dogan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"},{"name":"Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasemin","family":"Alanay","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Genetics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"},{"name":"Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"},{"name":"Department of Genome Studies, Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, 34752 Istanbul, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eda","family":"Tahir 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