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Science 23 December 1988:
Vol. 242. no. 4886, pp. 1702 - 1705
DOI: 10.1126/science.2849209
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Articles

Science, Vol 242, Issue 4886, 1702-1705
Copyright © 1988 by American Association for the Advancement of Science

articles

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

MR Hughes, PJ Malloy, DG Kieback, RA Kesterson, JW Pike, D Feldman, and BW O'Malley

Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030.

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.


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