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Endocrinology Vol. 142, No. 7 3135-3141
Copyright © 2001 by The Endocrine Society

ARTICLES

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

Olivier Dardenne, Josée Prud’homme, Alice Arabian, Francis H. Glorieux and René St-Arnaud2

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{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 D3. 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 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{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.




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