• insertion/substitution;
  • ligand binding;
  • vitamin D receptor;
  • resistance;
  • mutation


A young Chilean boy with severe rickets was found to have hereditary vitamin D-resistant rickets without alopecia. He had a unique insertion/substitution mutation in the ligand-binding domain of the vitamin D receptor. The in-frame mutation disrupted ligand binding and co-activator binding and resulted in 1,25(OH)2D3 resistance.

Introduction: Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor (VDR). In this study, we examined the VDR in a young boy who exhibited the typical clinical features of HVDRR but without alopecia.

Materials and Methods: The patient's VDR was studied using cultured dermal fibroblasts, and the recreated mutant VDR was analyzed in transfected cells.

Results: The patient's fibroblasts were resistant to 1,25-dihydroxyvitamin D [1,25(OH)2D3], exhibiting only a slight induction of 24-hydroxylase gene expression when treated with 1 μM 1,25(OH)2D3. [3H]1,25(OH)2D3 binding was absent in cell extracts from the patient's fibroblasts. Sequence analysis of the VDR gene uncovered a unique 5-bp deletion/8-bp insertion in exon 4. The mutation in helix H1 of the ligand-binding domain deletes two amino acids (H141 and T142) and inserts three amino acids (L141, W142, and A143). In transactivation assays, the recreated mutant VDR was 1000-fold less active than the wildtype (WT) VDR. In glutathione S-transferase (GST) pull-down assays, the mutant VDR bound GST-retinoid X receptor (RXR) weakly in the absence of 1,25(OH)2D3; however, the binding did not increase with increasing concentrations of ligand. The mutant VDR did not bind to GST-vitamin D receptor interacting protein (DRIP) 205 at concentrations up to 1 μM 1,25(OH)2D3. We also examined effects of the three individual mutations on VDR transactivation. Only the insertion of A143 into the WT VDR disrupted VDR transactivation to the same extent observed with the natural mutation.

Conclusion: We describe a novel insertion/substitution mutation in helix H1 of the VDR ligand-binding domain (LBD) that abolishes ligand binding and result in the syndrome of HVDRR. This is the first time an insertion/substitution has been found as the defect-causing HVDRR.