HEREDITARY 1-ALPHA,25-DIHYDROXYVITAMIN-D RESISTANT RICKETS RESULTING FROM A MUTATION IN THE VITAMIN-D RECEPTOR DEOXYRIBONUCLEIC ACID-BINDING DOMAIN

Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a genetic disease that results from mutations in the gene encoding the vitamin D receptor (VDR). In this study of two siblings showing classical features of HVDRR, cultured dermal fibroblasts were used to characterize their VDR and assess responsiveness to 1,25-dihydroxyvitamin D-3 treatment. The VDR displayed normal affinity and binding capacity for [H-3]1,25-dihydroxyvitamin D-3; however, the cells failed to exhibit induction of 25-hydroxyvitamin D 24-hydroxylase activity when treated with hormone. A decreased affinity of liganded VDR for DNA cellulose suggested that the defect was localized to the DNA-binding domain. Exons 2 and 3 of the VDR gene, which encode the two zinc fingers in the DNA-binding domain, were amplified and sequenced by polymerase chain reaction. Both siblings exhibited a G to A missense mutation (CGG to CAG) in exon 3, which results in the replacement of Arg(77) by Gln at the base of the second zinc finger. This mutation has been described previously in two unrelated cases of HVDRR by Sone ct at. It is unclear at this time whether these kindreds might be distantly related and, therefore, harbor the same mutation, or whether this represents a mutational hot spot in the VDR gene.