Targeted Inactivation of the 25-Hydroxyvitamin D3-1α-Hydroxylase Gene (CYP27B1) Creates an Animal Model of Pseudovitamin D-Deficiency Rickets1

Pseudovitamin D-deficiency rickets is caused by mutations in the cytochrome P450 enzyme, 25-hydroxyvitamin D3-1α-hydroxylase (1α-OHase). Patients with the disease exhibit growth retardation, rickets, and osteomalacia. Serum biochemistry is characterized by hypocalcemia, secondary hyperparathyroidism, and undetectable levels of 1α,25-dihydroxyvitamin D3. We have inactivated the 1α-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 1α,25-dihydroxyvitamin D3. Histological analysis of the bones from 3-week-old mutant animals confirmed the evidence of rickets. At the age of 8 weeks, femurs from 1α-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 1α-OHase gene in mice and established a valid animal model of pseudovitamin D-deficiency rickets.