Ab1359 Ccn6 Gene Mutation Induces Mitochondrial Dysfunction: The Cause of Progressive Pseudo-Pseudorheumatoid Dysplasia (Pprd)

Background: Progressive pseudo-pseudorheumatoid dysplasia (PPRD) is a rare autosomal recessive non-inflammatory joint disorder characterized by articular cartilage involvement, resulting in progressive joint stiffness and enlargement without inflammation [1]. The pathogenesis of PPRD remains elusive, although mutations in the cellular communication network factor 6 (CCN6) have been directly associated with this condition. Objectives: Revealing the molecular mechanism underlying PPRD triggered by CCN6 mutation. Methods: Exome sequencing was performed on a PPRD pedigree to identify potential mutations. A lentivirus-based expression vector containing the identified CCN6 mutation was constructed and utilized for chondrocyte infection to simulate the cellular pathology observed in PPRD. Co-immunoprecipitation, confocal imaging, Western blotting, and flow cytometry were employed to analyze changes in cellular function. Results: Both affected individuals within the pedigree, including the patient and her sister, were diagnosed with PPRD. Exome sequencing revealed that the most frequently reported CCN6 mutation site among published Chinese literature on PPRD was C223G. Subsequent cell transfection experiments demonstrated that wild-type CCN6 localized to chondrocyte mitochondria while CCN6 (C223G) remained cytoplasmic. Further investigation revealed impaired interaction between mutant CCN6-C223G and mitochondrial chaperone HSP60 compared to wild-type CCN6-HSP60 binding, leading to abnormal HSP60 function. This activation of mitochondrial unfolded protein response (mtUPR) disrupted cellular energy metabolism and resulted in altered gene expression within the nucleus. Conclusion: The identification of the CCN6-C223G mutation sheds light on its role in triggering mtUPR and subsequent aberrant chondrocyte function in PPRD patients. These findings provide valuable insights for potential drug development targeting this molecular pathway implicated in PPRD. REFERENCES: [1] Wynne-Davies R, Hall C, Ansell BM: Spondylo-epiphysial dysplasia tarda with progressive arthropathy. A "new" disorder of autosomal recessive inheritance. The Journal of bone and joint surgery British volume 1982, 64(4):442-445. Acknowledgements: NIL. Disclosure of Interests: None declared.