Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets

Academic Article


  • Hypocalcemic vitamin D-resistant rickets is a human genetic disease resulting from target organ resistance to the action of 1,25-dihydroxyvitamin D3. Two families with affected children homozygous for this autosomal recessive disorder were studied for abnormalities in the intracellular vitamin D receptor (VDR) and its gene. Although the receptor displays normal binding of 1,25-dihydroxyvitamin D3 hormone, VDR from affected family members has a decreased affinity for DNA. Genomic DNA isolated from these families was subjected to oligonucleotide-primed DNA amplification, and each of the nine exons encoding the receptor protein was sequenced for a genetic mutation. In each family, a different single nucleotide mutation was found in the DNA binding domain of the protein; one family near the tip of the first zinc finger (Gly→Asp) and one at the tip of the second zinc finger (Arg→Gly). The mutant residues were created in vitro by oligonucleotide directed point mutagenesis of wild-type VDR complementary DNA and this cDNA was transfected into COS-1 cells. The produced protein is biochemically indistinguishable from the receptor isolated from patients.
  • Published In

  • Science  Journal
  • Digital Object Identifier (doi)

    Author List

  • Hughes MR; Malloy PJ; Kieback DG; Kesterson RA; Pike JW; Feldman D; O'Malley BW
  • Start Page

  • 1702
  • End Page

  • 1705
  • Volume

  • 242
  • Issue

  • 4886