Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets

• Published in: Endocrinology (Philadelphia) Vol. 142; no. 7; pp. 3135 - 3141
• Main Authors: Dardenne, O, Prud'homme, J, Arabian, A, Glorieux, F H, St-Arnaud, R
• Format: Journal Article
• Language: English
• Published: United States 01.07.2001
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; Animals; Disease Models, Animal; Femur - pathology; Gene Expression - physiology; Gene Silencing - physiology; Gene Targeting; Hyperparathyroidism - etiology; Hypocalcemia - etiology; Hypophosphatemia - etiology; Mice; Mice, Inbred C57BL; Rickets - etiology; Rickets - pathology; Vitamin D - physiology; Vitamin D Deficiency - blood; Vitamin D Deficiency - complications; Vitamin D Deficiency - genetics
• ISSN: 0013-7227; 1945-7170

Pseudovitamin D-deficiency rickets is caused by mutations in the cytochrome P450 enzyme, 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-OHase). Patients with the disease exhibit growth retardation, rickets, and osteomalacia. Serum biochemistry is characterized by hypocalcemia, secondary hyperparathyroidism, and undetectable levels of 1alpha,25-dihydroxyvitamin D(3). We have inactivated the 1alpha-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 1alpha,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 1alpha-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 1alpha-OHase gene in mice and established a valid animal model of pseudovitamin D-deficiency rickets.