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Abnormal Binding of Vitamin D Receptors to Deoxyribonucleic Acid in a Kindred With Vitamin D-Dependent Rickets, Type II^*

Department of Medicine, Stanford University School of Medicine (P.J.M., D.F.) Stanford, California 94305
The Department of Pediatrics, Rambam Medical Center (Z.H.) Haifa, Israel
The Department of Pediatrics, Baylor College of Medicine (J.W.P.) Houston, Texas 77030

Address all correspondence and requests for reprints to: David Feldman, M.D., Division of Endocrinology, Stanford University School of Medicine, Stanford, California 94305.

Vitamin D-dependent rickets, type II, is a hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃]. We describe here a family (designated G) with a defect in the DNA-binding domain of the 1,25-(OH)₂D receptor (VDR) manifested by normal steroid binding and decreased VDR affinity for DNA. The phenotypically normal parents are heterozygous, expressing both normal and defective forms of VDR. The affected children in this family had early-onset rickets, alopecia, hypocalcemia, and elevated serum 1,25-(OH)₂D₃ levels. The VDR of cultured skin fibroblasts of the affected children (Gl and G2) as well as the parents (G3 and G4) bound [³H]1,25-(OH)₂D₃ normally (K_d = 2–3 x 10^–11 mol/L; maximal number of binding sites = 20–40 fmol/mg protein). The cells from Gl and G2 were resistant to 1,25-(OH)₂D₃ action, as measured by induction of 24-hydroxylase activity, while the cells from G3 and G4 responded normally. Western blot analysis using the anti-VDR monoclonal antibody 9A7 showed that hypertonic extracts of fibroblasts from both affected children (Gl and G2) and their parents (G3 and G4) had immunoreactive bands of 48K, identical to the size of the VDR in normal cells. The VDR from Gl and G2 eluted as a single peak from DNA-cellulose columns at a lower salt concentration (0.1 mol/L) than that from normal subjects (0.2 mol/L), indicating an apparent decreased affinity for DNA. Fibroblast VDR from G3 and G4 each eluted from DNA-cellulose columns as two peaks, the normal peak (0.2 mol/L) and the abnormal peak (0.1 mol/L), which was found in Gl and G2. Western blot analysis of the 0.1 and 0.2 mol/L KC1 peak fractions also confirmed that VDR was present in only the 0.1 mol/L fraction and not the 0.2 mol/L fraction from Gl. However, VDR was present in both fractions from G3. In summary, this vitamin Ddependent rickets, type II, kindred has a defect in the DNA-binding domain of VDR. The parents are phenotypically normal and express both the normal and defective VDR alleles, as demonstrated by both DNA-cellulose chromatography and Western blot analysis. The affected children are resistant to 1,25-(OH)₂D₃ action and are homozygous for the defective VDR.

^* This work was supported by NIH Grant AG-01312 (to D.F.), March of Dimes Grant 1-1009 (to J.W.P.) and National Research Service Award DK-07882 (to P.J.M.).

Received June 5, 1988.

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