Targeted inactivation of the 25-hydroxyvitamin D3-1α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets
Targeted inactivation of the 25-hydroxyvitamin D3-1α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets
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DOI：
10.1210/en.142.7.3135
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发表时间：
2001-07-01
期刊：
影响因子：
4.8
通讯作者：
St-Arnaud, R
中科院分区：
文献类型：
--
作者：
Dardenne, O;Prud'homme, J;St-Arnaud, R
假性维生素D缺乏性佝偻病是由细胞色素P450酶，25-羟基维生素D-3-1 α-羟化酶（1 α-OH酶）突变引起的。患有该疾病的患者表现出生长迟缓、佝偻病和骨软化。血清生化特征为低钙血症、继发性甲状旁腺功能亢进和1 α，25-二羟维生素D-3检测不到。我们在小鼠胚胎干细胞中同源重组后使1 α-OHase基因失活.纯合子突变动物的血清分析证实，它们是低钙血症、低磷酸盐血症、高甲状旁腺素血症，并且它们具有不可检测的1 α，25-二羟维生素D-3。对3周龄的突变动物的骨骼进行组织学分析，证实了佝偻病的证据。在8周龄时，来自1 α-OH酶消融小鼠的股骨在生长板的结构中呈现严重的紊乱和显著的骨软化。这些结果表明，我们成功地灭活了小鼠1 α-OHase基因，并建立了一个有效的假性维生素D缺乏性佝偻病动物模型。
Pseudovitamin D-deficiency rickets is caused by mutations in the cytochrome P450 enzyme, 25-hydroxyvitamin D-3-1 alpha -hydroxylase (1 alpha -OHase). Patients with the disease exhibit growth retardation, rickets, and osteomalacia. Serum biochemistry is characterized by hypocalcemia, secondary hyperparathyroidism, and undetectable levels of 1 alpha ,25-dihydroxyvitamin D-3. We have inactivated the 1 alpha -OHase gene in mice after homologous recombination in embryonic stem cells. Serum analysis of homozygous mutant animals confirmed that they were hypocalcemic, hypophosphatemic, hyperparathyroidic, and that they had undetectable 1 alpha ,25-dihydroxyvitamin D-3. Histological analysis of the bones from 3-week-old mutant animals confirmed the evidence of rickets. At the age of 8 weeks, femurs from 1 alpha -OHase-ablated mice present a severe disorganization in the architecture of the growth plate and marked osteomalacia. These results show that we have successfully inactivated the 1 alpha -OHase gene in mice and established a valid animal model of pseudovitamin D-deficiency rickets.