Impact of the mutation on bone mineralization and ectopic calcification: evidence from and models.

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 the Y451C mutation in diffuse idiopathic skeletal hyperostosis patients, but its precise impact on bone mineralization and ectopic calcification remains unclear.

METHODS

We used bioinformatics tools and functional assays to assess the impact of the Y451C 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 and assays showed that the Y451C mutation affects the protein's structure, reducing enzymatic activity by approximately 50%. We successfully generated the knock-in mouse model. However, no significant differences were observed in body phenotype or biochemical markers in mice 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

The Y451C mutation significantly reduces enzymatic activity , yet the knock-in mouse model shows no significant abnormalities in mineralization, providing additional evidence for the pathogenicity assessment of Y451C variant. Given that these results are from mouse models, further studies are required to clarify its pathogenicity in humans.