Targeted inactivation of the 25-hydroxyvitamin D3-1α-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets

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.