Functional characterization of a rare pathogenic variant c.875G > A, p.(Cys292Tyr) in COMP

The protein encoded by the cartilage oligomeric matrix protein (COMP) gene is a noncollagenous extracellular matrix (ECM) protein that is important for chondrocyte formation and growth. Variations in the COMP gene cause pseudoachondroplasia (PSACH), which is mainly characterized by short-limbed dwarfing in the clinic.To characterize the function of a rare pathogenic variant in the COMP gene (c.875G > A, p.Cys292Tyr).We performed 3D structural analysis, in vitro expression analysis, and immunofluorescence to characterize the effects of the variant on protein structure, expression, and cellular localization respectively.Variation modeling showed that the interactions between amino acids were changed after the variation, and there were 31 changes in the secondary structure of mutant COMP (MT-COMP). Western blot showed that the intracellular quantity of MT-COMP was higher than the wild-type COMP (WT-COMP). Cellular immunofluorescence results showed that WT-COMP was less abundant and homogenously distributed in cells, while the MT-COMP accumulated in the cytoplasm.Herein, we report a variant of COMP in a Chinese family with PSACH. We have shown that the rare missense variant, COMP c.875G > A, previously reported in ClinVar and identified in our patient, results in excessive accumulation of mutant protein in the cytoplasm, and is therefore pathogenic.Through in silico and experimental analyses, we provide evidence that COMP c.875G > A is the likely cause of PSACH in a Chinese family.