Wu Wanhong, Liu Luna, Shi Yingzhou, Zhang Yidan, Qiu Renyuan, Yan Fang
Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Department of Radiology, Shandong Rongjun General Hospital, Jinan, Shandong, China.
Front Endocrinol (Lausanne). 2025 Jun 4;16:1566392. doi: 10.3389/fendo.2025.1566392. eCollection 2025.
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.
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.
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.
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.
外核苷酸焦磷酸酶/磷酸二酯酶1（）在矿化过程中起关键作用，该基因的突变与多种严重疾病相关。临床病例报告表明弥漫性特发性骨肥厚患者存在Y451C突变，但其对骨矿化和异位钙化的确切影响尚不清楚。
我们使用生物信息学工具和功能测定来评估Y451C突变对蛋白质结构和酶活性的影响。此外，我们构建了一个敲入小鼠模型（），通过显微CT评估微观结构或异位钙化迹象。
生物信息学分析和测定表明，Y451C突变影响蛋白质的结构，使酶活性降低约50%。我们成功构建了敲入小鼠模型。然而，与野生型对照相比，在3、5和10个月时，敲入小鼠的身体表型或生化标志物未观察到显著差异。同样，在骨微观结构或异位钙化迹象方面也未观察到显著变化。
Y451C突变显著降低酶活性，然而敲入小鼠模型在矿化方面未显示出显著异常，为Y451C变异体的致病性评估提供了额外证据。鉴于这些结果来自小鼠模型，需要进一步研究以阐明其在人类中的致病性。
