title: Vitamin D receptors from patients with resistance to 1,25-dihydroxyvitamin D3: point mutations confer reduced transactivation in response to ligand and impaired interaction with the retinoid X receptor heterodimeric partner.
abstract: Hereditary hypocalcemic vitamin D-resistant rickets is attributable to defects in the nuclear receptor for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Two novel point mutations (I314S and R391C) identified in the hormone-binding domain of the human vitamin D receptor (VDR) from patients with hereditary hypocalcemic vitamin D-resistant rickets confer the receptor with sharply reduced 1,25-(OH)2D3-dependent transactivation. These natural mutations, especially R391C, also lead to a second specific consequence, namely impaired heterodimeric interaction with retinoid X receptor (RXR). While the transactivation ability of the I314S mutant can be largely restored by providing excess 1,25-(OH)2D3, R391C activity is more effectively restored with exogenous RXR. These observations are reflected also in the clinical course of each patient: the patient bearing the I314S mutation showed a nearly complete cure with pharmacological doses of a vitamin D derivative, whereas the patient bearing R391C responded only partially to such therapy. Further tests with patient fibroblasts and transfected cells show that the activity of the I314S VDR mutant is augmented somewhat by added RXR, while transactivation by the R391C mutant is best corrected by RXR in the presence of excess hormone. Thus, the effects of hormone vs. RXR in bolstering these mutant VDRs, such that they mediate efficient transactivation, are not entirely separable. The unique properties of these genetically altered receptors establish a new subclass of natural human VDR mutants that illustrate, in vivo, the importance of both 1,25-(OH)2D3 binding and heterodimerization with RXR in VDR action.
authors.affiliation: Department of Biochemistry, University of Arizona College of Medicine, Tucson 85724, USA.
authors.forename: G K
authors.initials: GK
authors.lastname: Whitfield
authors.forename: S H
authors.initials: SH
authors.lastname: Selznick
authors.forename: C A
authors.initials: CA
authors.lastname: Haussler
authors.forename: J C
authors.initials: JC
authors.lastname: Hsieh
authors.forename: M A
authors.initials: MA
authors.lastname: Galligan
authors.forename: P W
authors.initials: PW
authors.lastname: Jurutka
authors.forename: P D
authors.initials: PD
authors.lastname: Thompson
authors.forename: S M
authors.initials: SM
authors.lastname: Lee
authors.forename: J E
authors.initials: JE
authors.lastname: Zerwekh
authors.forename: M R
authors.initials: MR
authors.lastname: Haussler
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002675:Child, Preschool; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D006996:Hypocalcemia / Q000188:drug therapy / Q000235:genetics; D007223:Infant; D008659:Metabolic Diseases / Q000235:genetics; D008969:Molecular Sequence Data; D010641:Phenotype; D017354:Point Mutation; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002117:Calcitriol