Impact of themutation on bone mineralization and ectopic calcification: evidence fromandmodels.

Abstract

BACKGROUND: Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 () plays a key role in mineralization processes, and mutations in this gene are associated with various severe diseases. Clinical case reports have implicated theY451C mutation in diffuse idiopathic skeletal hyperostosis patients, but its precise impact on bone mineralization and ectopic calcification remains unclear. METHODS: We used bioinformatics tools andfunctional assays to assess the impact of theY451C mutation on protein structure and enzymatic activity. Furthermore, we generated a knock-in mouse model () to evaluate microarchitecture or signs of ectopic calcification by Micro-CT. RESULTS: Bioinformatics analysis andassays showed that the Y451C mutation affects theprotein's structure, reducing enzymatic activity by approximately 50%. We successfully generated theknock-in mouse model. However, no significant differences were observed in body phenotype or biochemical markers inmice at 3, 5, and 10 months, compared to wild-type controls. Similarly, no significant changes were observed in bone microarchitecture or signs of ectopic calcification. CONCLUSION: TheY451C mutation significantly reduces enzymatic activity, yet theknock-in mouse model shows no significant abnormalities in mineralization, providing additional evidence for the pathogenicity assessment ofY451C variant. Given that these results are from mouse models, further studies are required to clarify its pathogenicity in humans.