A unique point mutation in the human vitamin d receptor chromosomal gene confers hereditary resistance to 1, 25-dihydroxyvitamin D3

Teruki Sone, Stephen J. Marx, Uri A. Liberman, J. Wesley Pike

Research output: Contribution to journalArticlepeer-review

Abstract

The syndrome of hereditary resistance to 1, 25-dihydroxyvitamin D3 is due to defective function of the vitamin D receptor (VDR). The recent cloning and nucleotide sequence determination of the human VDR chromosomal gene have enabled a direct evaluation of the genetic basis for this disease in affected patients. In this report we employed polymerase chain reaction techniques to amplify the gene exons that encode the DNA-binding domain of the VDR from two 1, 25-dihydroxy vitamin D3-resistant patients whose receptors displayed defective binding to nonspecific DNA. Although their families were apparently unrelated, each patient displayed an identical homozygous point mutation within the third exon, a mutation that causes substitution of a glutamine for an arginine residue highly conserved within the entire steroid receptor superfamily. We introduced this base change into the normal VDR cDNA via site-directed mutagenesis, transfected an expression vector containing this cDNA into cells, and examined the functional properties of the resultant VDR expression product. The produced mutant receptor bound 1, 25-dihydroxy vitamin D3 with normal affinity, but displayed weak affinity for the nuclear fraction and for heterologous DNA. More importantly, the protein was inactive in promoting transcription in a cotransfection assay employing a chloramphenicol acetyltransferase gene reporter fused down-stream of the VDR-inducible osteocalcin gene promoter-enhancer. These results provide the genetic and functional basis for the phenotype of rickets in this inherited disease.

Original languageEnglish
Pages (from-to)623-631
Number of pages9
JournalMolecular Endocrinology
Volume4
Issue number4
DOIs
StatePublished - Apr 1990

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