biostudies-literatureGuven Tasbicen GAcıbadem UniversityScientific and Technological Research Council of Turkey8838https://www.ebi.ac.uk/biostudies/studies/S-EPMC12469775biostudies-literatureUnknown26(18)Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive cartilage disorder caused by biallelic variants in <i>CCN6</i>, 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 <i>CCN6</i> variants affect chondrocyte function, we overexpressed four variants-p.Cys52*, p.Tyr109*, p.Gly83Glu, and p.Cys114Trp-all located within the IGFBP domain, and evaluated their impact on parameters including redox balance, ER stress, ECM remodeling, gene expression, and protein-protein interactions. The p.Cys52* variant resulted in rapid degradation of WISP3, indicating a complete loss-of-function. The p.Tyr109* variant disrupted International journal of molecular sciencesMolecular Consequences of <i>CCN6</i> Variants Encoding WISP3 in Progressive Pseudorheumatoid Dysplasia.PMC124697752024-2170222S011Guven Tasbicen GSavsar BAlanay YTonbul ZBulbul ATufan AOnat UIGuzel ETahir Turanli EAyhan DHTimucin ACBayram Akcapinar GAkgun Dogan OfalseMolecular Consequences of <i>CCN6</i> Variants Encoding WISP3 in Progressive Pseudorheumatoid Dysplasia.Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive cartilage disorder caused by biallelic variants in <i>CCN6</i>, 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 <i>CCN6</i> variants affect chondrocyte function, we overexpressed four variants-p.Cys52*, p.Tyr109*, p.Gly83Glu, and p.Cys114Trp-all located within the IGFBP domain, and evaluated their impact on parameters including redox balance, ER stress, ECM remodeling, gene expression, and protein-protein interactions. The p.Cys52* variant resulted in rapid degradation of WISP3, indicating a complete loss-of-function. The p.Tyr109* variant disrupted 2025-01-01T00:00:00Z2025 Sep2026-07-04T03:14:43.263Z2026-07-04T03:12:56.531ZS-EPMC124697754100940710.3390/ijms26188838