Desbuquois dysplasia (DD) type 1 is a rare skeletal dysplasia characterized by a short stature, round face, progressive scoliosis, and joint laxity. The causative gene has been identified as calcium‐activated nucleotidase 1 (CANT1), which encodes a nucleotidase that preferentially hydrolyzes UDP to UMP and phosphate. In this study, we generated Cant1 KO mice using CRISPR/Cas9‐mediated genome editing. All F0 mice possessing frameshift deletions at both Cant1 alleles exhibited a dwarf phenotype. Germline transmission of the edited allele was confirmed in an F0 heterozygous mouse, and KO mice were generated by crossing of the heterozygous breeding pairs. Cant1 KO mice exhibited skeletal defects, including short stature, thoracic kyphosis, and delta phalanx, all of which are observed in DD type 1 patients. The glycosaminoglycan (GAG) content and extracellular matrix space were reduced in the growth plate cartilage of mutants, and proliferating chondrocytes lost their typical flat shape and became round. Chondrocyte differentiation, especially terminal differentiation to hypertrophic chondrocytes, was impaired in Cant1 KO mice. These findings indicate that CANT1 is involved in the synthesis of GAG and regulation of chondrocyte differentiation in the cartilage and contribute to a better understanding of the pathogenesis of DD type 1.

中文翻译：

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在Desbuquois发育异常的小鼠模型中CANT1缺乏会损害糖胺聚糖的合成以及生长板软骨中软骨细胞的分化。

1型Desbuquois发育不良（DD）是一种罕见的骨骼发育不良，其特征是身材矮小，圆脸，进行性脊柱侧弯和关节松弛。致病基因已被鉴定为钙激活的核苷酸酶1（CANT1），它编码一种核苷酸酶，该酶优先将UDP水解为UMP和磷酸盐。在这项研究中，我们使用CRISPR / Cas9介导的基因组编辑生成了Cant1 KO小鼠。所有在两个Cant1等位基因处都具有移码缺失的F0小鼠表现出矮表型。在F0杂合小鼠中证实了编辑的等位基因的种系传递，并且通过杂合育种对的杂交产生了KO小鼠。不能1KO小鼠表现出骨骼缺陷，包括身材矮小，胸椎后凸畸形和三角骨趾骨，所有这些都在DD 1型患者中观察到。突变体的生长板软骨中的糖胺聚糖（GAG）含量和细胞外基质空间减少，并且增殖的软骨细胞失去了典型的扁平形状而变成圆形。Cant1 KO小鼠的软骨细胞分化，特别是向肥大软骨细胞的终末分化受到损害。这些发现表明，CANT1参与了GAG的合成和软骨细胞分化的调控，并有助于更好地了解DD型1的发病机理。