TARGETED ABLATION OF THE VITAMIN-D-RECEPTOR - AN ANIMAL-MODEL OF VITAMIN-D-DEPENDENT RICKETS TYPE-II WITH ALOPECIA

Vitamin D, the major steroid hormone that controls mineral ion homeost asis, exerts its actions through the vitamin D receptor (VDR), The VDR is expressed in many tissues, including several tissues not thought t o play a role in mineral metabolism, Studies in kindreds with VDR muta tions (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopeci a, which is not a feature of vitamin D deficiency, is seen in some kin dreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite know n expression of the VDR in fetal life, homozygous mice are phenotypica lly normal at birth and demonstrate normal survival at least until 6 m onths. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise, Hyperparathyroidism i s accompanied by an increase in the size of the parathyroid gland as w ell as an increase in PTH mRNA levels. Rickets and osteomalacia are se en by day 35; however, as early as day 15, there is an expansion in th e zone of hypertrophic chondrocytes in the growth plate. In contrast t o animals made vitamin D deficient by dietary means, and like some pat ients with VDDR IT, these mice develop progressive alopecia from the a ge of 4 weeks.