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A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia

Department of Medicine (P.J.M., R.X., L.P., D.F.), Stanford University School of Medicine, Stanford, California 94305; and Department of Pediatrics (P.A.C.), University of Louisville, Louisville, Kentucky 40202

Address all correspondence and requests for reprints to: David Feldman, M.D., Stanford University School of Medicine, Division of Endocrinology, Gerontology and Metabolism, Stanford University Medical Center, Room S005, Stanford, California 94305-5103.

Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)₂D₃]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [³H]1,25-(OH)₂D₃ in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)₂D₃ or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)₂D₃-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.

NURSA Molecule Pages Link:

Nuclear Receptors:   VDR  |  RXRα

Coregulators:   TRAP220  |  SRC-1

Ligands:   Calcitriol

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