Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix.

中文翻译：

---

钙激活的核苷酸酶1（CANT1）对于软骨和软骨内骨化中糖胺聚糖的生物合成至关重要。

1型Desbuquois不典型增生（DBQD1）是由于CANT1基因中的突变引起的软骨发育不良，该CANT1基因编码水解UDP的ER /高尔基钙激活核苷酸酶1。在这里，我们使用Cant1基因敲除和敲除DBQD1表型的小鼠，我们报告CANT1在软骨蛋白聚糖合成和软骨内骨化中起着至关重要的作用。具体来说，Cant1基因敲除小鼠的软骨细胞中糖胺聚糖的合成减少，它们的流体动力学大小减小，而硫酸化作用增加，蛋白聚糖的整体分泌被延迟。有趣的是，敲除的软骨细胞已经扩张了ER池，表明蛋白分泌延迟和细胞应激。然而，使用微阵列分析，Xbp1剪接和BiP和ATF4的蛋白水平均未检测到典型的ER应激反应。观察到的蛋白聚糖缺陷导致生长板中软骨细胞的增殖和成熟失调，导致骨骼生长减少。总之，DBQD1的致病机理包括由于缺陷的细胞内蛋白聚糖合成和改变细胞外基质中蛋白聚糖特性而导致的软骨细胞性能失调。