Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-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)-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.
Dardenne
O
O
Genetics Unit, Shriners Hospital for Children, Montréal, Quebéc, Canada H3G 1A6.
Prud'homme
J
J
Arabian
A
A
Glorieux
F H
FH
St-Arnaud
R
R
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D005269:Femur / Q000473:pathology; D015870:Gene Expression / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology*; D018390:Gene Targeting; D006961:Hyperparathyroidism / Q000209:etiology; D006996:Hypocalcemia / Q000209:etiology; D017674:Hypophosphatemia / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D012279:Rickets / Q000209:etiology* / Q000473:pathology; D014807:Vitamin D / Q000502:physiology; D014808:Vitamin D Deficiency / Q000097:blood / Q000150:complications* / Q000235:genetics*
D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase