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-Hydroxylase Gene (CYP27B1) Creates an Animal Model of Pseudovitamin D-Deficiency Rickets1
Genetics Unit (O.D., J.P., A.A., F.H.G., R.St.-A.), Shriners Hospital for Children, Montréal (Quebéc) Canada H3G 1A6; and Departments of Surgery and Human Genetics (F.H.G., R.St.-A.), McGill University, Montréal (Québec) Canada H3A 1B1
Address all correspondence and requests for reprints to: René St-Arnaud, Genetics Unit, Shriners Hospital for Children, 1529 Cedar Avenue, Montréal (Québec), Canada H3G 1A6. E-mail: rst-arnaud{at}shriners.mcgill.ca
Pseudovitamin D-deficiency rickets is caused by mutations in the
cytochrome P450 enzyme, 25-hydroxyvitamin
D3-1
-hydroxylase (1-OHase). Patients with the disease
exhibit growth retardation, rickets, and osteomalacia. Serum
biochemistry is characterized by hypocalcemia, secondary
hyperparathyroidism, and undetectable levels of
1,25-dihydroxyvitamin D3. We have inactivated the
1-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 1,25-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
1-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-OHase gene in mice
and established a valid animal model of pseudovitamin D-deficiency
rickets.
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