Huber Céline, Oulès Bénédicte, Bertoli Marta, Chami Mounia, Fradin Mélanie, Alanay Yasemin, Al-Gazali Lihadh I, Ausems Margreet G E M, Bitoun Pierre, Cavalcanti Denise P, Krebs Alexander, Le Merrer Martine, Mortier Geert, Shafeghati Yousef, Superti-Furga Andrea, Robertson Stephen P, Le Goff Carine, Muda Andrea Onetti, Paterlini-Bréchot Patrizia, Munnich Arnold, Cormier-Daire Valérie
Paris Descartes University, Department of Genetics and INSERM U781 and U807, Hôpital Necker Enfants Malades, 75015 Paris, France.
Am J Hum Genet. 2009 Nov;85(5):706-10. doi: 10.1016/j.ajhg.2009.10.001. Epub 2009 Oct 22.
Desbuquois dysplasia is a severe condition characterized by short stature, joint laxity, scoliosis, and advanced carpal ossification with a delta phalanx. Studying nine Desbuquois families, we identified seven distinct mutations in the Calcium-Activated Nucleotidase 1 gene (CANT1), which encodes a soluble UDP-preferring nucleotidase belonging to the apyrase family. Among the seven mutations, four were nonsense mutations (Del 5' UTR and exon 1, p.P245RfsX3, p.S303AfsX20, and p.W125X), and three were missense mutations (p.R300C, p.R300H, and p.P299L) responsible for the change of conserved amino acids located in the seventh nucleotidase conserved region (NRC). The arginine substitution at position 300 was identified in five out of nine families. The specific function of CANT1 is as yet unknown, but its substrates are involved in several major signaling functions, including Ca2+ release, through activation of pyrimidinergic signaling. Importantly, using RT-PCR analysis, we observed a specific expression in chondrocytes. We also found electron-dense material within distended rough endoplasmic reticulum in the fibroblasts of Desbuquois patients. Our findings demonstrate the specific involvement of a nucleotidase in the endochondral ossification process.
德布凯发育不良是一种严重病症，其特征为身材矮小、关节松弛、脊柱侧弯以及伴有三角形指骨的腕骨骨化提前。通过对九个德布凯家族的研究，我们在钙激活核苷酸酶1基因（CANT1）中鉴定出七个不同的突变，该基因编码一种属于腺苷三磷酸双磷酸酶家族的偏好UDP的可溶性核苷酸酶。在这七个突变中，四个为无义突变（5'UTR和外显子1缺失、p.P245RfsX3、p.S303AfsX20和p.W125X），三个为错义突变（p.R300C、p.R300H和p.P299L），这些突变导致位于第七个核苷酸酶保守区域（NRC）的保守氨基酸发生改变。在九个家族中的五个家族中都鉴定出了第300位的精氨酸替代。CANT1的具体功能尚不清楚，但其底物参与了包括通过激活嘧啶能信号传导实现的Ca2+释放在内的几种主要信号传导功能。重要的是，通过逆转录聚合酶链反应（RT-PCR）分析，我们观察到其在软骨细胞中有特异性表达。我们还在德布凯患者的成纤维细胞中扩张的粗面内质网内发现了电子致密物质。我们的研究结果表明一种核苷酸酶在软骨内骨化过程中具有特异性作用。
