Molecular Consequences of CCN6 Variants Encoding WISP3 in Progressive Pseudorheumatoid Dysplasia

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive cartilage disorder caused by biallelic variants in CCN6, encoding the matricellular protein WISP3. To investigate how disease-associated CCN6 variants impact chondrocytes, we overexpressed two clinically relevant variants—p.Cys52* and p.Cys114Trp—both located in the IGFBP domain, and assessed their effects on redox balance, ER stress, ECM remodeling, gene expression, and protein–protein interactions. The p.Cys52* variant led to rapid degradation of WISP3, consistent with complete loss-of-function. In contrast, p.Cys114Trp induced severe protein destabilization, mitochondrial ROS accumulation, and elevated ER stress. Proteomic analysis revealed that p.Cys114Trp established novel interactions, suggesting a gain-of-function effect. These variant-specific differences highlight how structural context influences cellular outcomes beyond variant type alone. Altogether, our findings emphasize the necessity of functional characterization to better model PPD pathogenesis and provide mechanistic insights that may guide future therapeutic strategies.