Compound heterozygous mutations in the vitamin D receptor in a patient with hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia.

Hereditary vitamin D-resistant rickets (HVDRR) is a rare recessive genetic disorder caused by mutations in the vitamin D receptor (VDR). In this study, we examined the VDR in a young girl with clinical features of HVDRR including rickets, hypophosphatemia, and elevated serum 1,25(OH)(2)D. The girl also had total alopecia. Two mutations were found in the VDR gene: a nonsense mutation (R30X) in the DNA-binding domain and a unique 3-bp in-frame deletion in exon 6 that deleted the codon for lysine at amino acid 246 (DeltaK246). The child and her mother were both heterozygous for the 3-bp deletion, whereas the child and her father were both heterozygous for the R30X mutation. Fibroblasts from the patient were unresponsive to 1,25(OH)(2)D(3) as shown by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)(2)D(3) responsiveness. [(3)H]1,25(OH)(2)D(3) binding and immunoblot analysis showed that the patient's cells expressed the VDRDeltaK246 mutant protein; however, the amount of VDRDeltaK246 mutant protein was significantly reduced compared with wildtype controls. In transactivation assays, the recreated VDRDeltaK246 mutant was unresponsive to 1,25(OH)(2)D(3). The DeltaK246 mutation abolished heterodimerization of the mutant VDR with RXRalpha and binding to the coactivators DRIP205 and SRC-1. However, the DeltaK246 mutation did not affect the interaction of the mutant VDR with the corepressor Hairless (HR). In summary, we describe a patient with compound heterozygous mutations in the VDR that results in HVDRR with alopecia. The R30X mutation truncates the VDR, whereas the DeltaK246 mutation prevents heterodimerization with RXR and disrupts coactivator interactions.