title: Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets.
abstract: 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.
authors.affiliation: Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030.
authors.forename: M R
authors.initials: MR
authors.lastname: Hughes
authors.forename: P J
authors.initials: PJ
authors.lastname: Malloy
authors.forename: D G
authors.initials: DG
authors.lastname: Kieback
authors.forename: R A
authors.initials: RA
authors.lastname: Kesterson
authors.forename: J W
authors.initials: JW
authors.lastname: Pike
authors.forename: D
authors.initials: D
authors.lastname: Feldman
authors.forename: B W
authors.initials: BW
authors.lastname: O'Malley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D003062:Codon; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005091:Exons; D005260:Female; D005784:Gene Amplification; D006720:Homozygote; D006801:Humans; D006996:Hypocalcemia / Q000235:genetics*; D015151:Immunoblotting; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D012279:Rickets / Q000235:genetics*; D014162:Transfection
chemical_list: D003062:Codon; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D004247:DNA; D002117:Calcitriol