Molecular Consequences of CCN6 Variants Encoding WISP3 in Progressive Pseudorheumatoid Dysplasia.

ABSTRACT: 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-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

SUBMITTER: Guven Tasbicen G 

PROVIDER: S-EPMC12469775 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature