VDR is expressed in most tissues of the body, and regulates transcription of genes involved inintestinal andrenal transport ofcalcium and other minerals.[8]Glucocorticoids decrease VDR expression.[8] Many types of immune cells also express VDR.[9]
The VDR gene encodes the nuclear hormone receptor for vitamin D. The most potent natural agonist is calcitriol (1,25-dihydroxycholecalciferol) and the vitamin D2 homologue ercalcitriol, 1-alpha,25-dihydroergocalciferol) is also a strong activator. Other forms of vitamin D bind with lower affinity, as does the secondarybile acidlithocholic acid. The receptor belongs to the family of trans-acting transcriptional regulatory factors and shows similarity of sequence to the steroid and thyroid hormone receptors.[10]
Downstream targets of this nuclear hormone receptor include many genes involved in mineral metabolism.[8] The receptor regulates a variety of other metabolic pathways, such as those involved in the immune response and cancer.[9] VDR variants that bolster vitamin-D action and that are directly correlated with AIDS progression rates and VDR association with progression to AIDS follows an additive model.[11] FokI polymorphism is a risk factor for enveloped virus infection as revealed in a meta-analysis.[12] The importance of this gene has also been noted in the natural aging process were 3’UTR haplotypes of the gene showed an association with longevity.[13]
Mutations in this gene are associated with type II vitamin D-resistantrickets. A single nucleotide polymorphism in the initiation codon results in an alternate translation start site three codons downstream. Alternative splicing results in multiple transcript variants encoding the same protein.[14] VDR gene variants seem to influence many biological endpoints, including those related to osteoporosis[15]
The vitamin D receptor plays an important role in regulating the hair cycle. Loss of VDR is associated with hair loss in experimental animals.[16] Experimental studies have shown that the unliganded VDR interacts with regulatory regions in cWnt (wnt signaling pathway) andsonic hedgehog target genes and is required for the induction of these pathways during the postnatal hair cycle.[17] These studies have revealed novel actions of the unliganded VDR in regulating the post-morphogenic hair cycle.
Researchers have focused their efforts in elucidating the role of VDR polymorphisms in different diseases and normal phenotypes such as the HIV-1 infection susceptibility and progression or the natural aging process. The most remarkable findings include the report of VDR variants that bolster vitamin-D action and that are directly correlated with AIDS progression rates, that VDR association with progression to AIDS follows an additive model[11] and the role of FokI polymorphism as a risk factor for enveloped virus infection as revealed in a meta-analysis.[12]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Moore DD, Kato S, Xie W, Mangelsdorf DJ, Schmidt DR, Xiao R, Kliewer SA (December 2006). "International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor".Pharmacol. Rev.58 (4):742–59.doi:10.1124/pr.58.4.6.PMID17132852.S2CID85996383.
^Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF (September 1991). "The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7".Genomics.11 (1):168–73.doi:10.1016/0888-7543(91)90114-T.PMID1662663.
^abAdorini L, Daniel KC, Penna G (2006). "Vitamin D receptor agonists, cancer and the immune system: an intricate relationship".Curr Top Med Chem.6 (12):1297–301.doi:10.2174/156802606777864890.PMID16848743.
^Germain P, Staels B, Dacquet C, Spedding M, Laudet V (December 2006). "Overview of nomenclature of nuclear receptors".Pharmacol. Rev.58 (4):685–704.doi:10.1124/pr.58.4.2.PMID17132848.S2CID1190488.
^abLaplana M, Sánchez-de-la-Torre M, Puig T, Caruz A, Fibla J (July 2014). "Vitamin-D pathway genes and HIV-1 disease progression in injection drug users".Gene.545 (1):163–9.doi:10.1016/j.gene.2014.04.035.hdl:10459.1/67999.PMID24768180.
^Laplana M, Sánchez-de-la-Torre M, Aguiló A, Casado I, Flores M, Sánchez-Pellicer R, Fibla J (April 2010). "Tagging long-lived individuals through vitamin-D receptor (VDR) haplotypes".Biogerontology.11 (4):437–46.doi:10.1007/s10522-010-9273-8.hdl:10459.1/67920.PMID20407924.S2CID34809120.
^abTagami T, Lutz WH, Kumar R, Jameson JL (December 1998). "The interaction of the vitamin D receptor with nuclear receptor corepressors and coactivators".Biochem. Biophys. Res. Commun.253 (2):358–63.Bibcode:1998BBRC..253..358T.doi:10.1006/bbrc.1998.9799.PMID9878542.
^abcdPuccetti E, Obradovic D, Beissert T, Bianchini A, Washburn B, Chiaradonna F, Boehrer S, Hoelzer D, Ottmann OG, Pelicci PG, Nervi C, Ruthardt M (December 2002). "AML-associated translocation products block vitamin D(3)-induced differentiation by sequestering the vitamin D(3) receptor".Cancer Res.62 (23):7050–8.PMID12460926.
Goto H, Chen KS, Prahl JM, DeLuca HF (1992). "A single receptor identical with that from intestine/T47D cells mediates the action of 1,25-dihydroxyvitamin D-3 in HL-60 cells".Biochim. Biophys. Acta.1132 (1):103–8.doi:10.1016/0167-4781(92)90063-6.PMID1324736.
Szpirer J, Szpirer C, Riviere M, Levan G, Marynen P, Cassiman JJ, Wiese R, DeLuca HF (1992). "The Sp1 transcription factor gene (SP1) and the 1,25-dihydroxyvitamin D3 receptor gene (VDR) are colocalized on human chromosome arm 12q and rat chromosome 7".Genomics.11 (1):168–73.doi:10.1016/0888-7543(91)90114-T.PMID1662663.
Hughes MR, Malloy PJ, Kieback DG, Kesterson RA, Pike JW, Feldman D, O'Malley BW (1989). "Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets".Science.242 (4886):1702–5.doi:10.1126/science.2849209.PMID2849209.
Rut AR, Hewison M, Kristjansson K, Luisi B, Hughes MR, O'Riordan JL (1995). "Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures".Clin. Endocrinol.41 (5):581–90.doi:10.1111/j.1365-2265.1994.tb01822.x.PMID7828346.S2CID40851942.
Malloy PJ, Weisman Y, Feldman D (1994). "Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets resulting from a mutation in the vitamin D receptor deoxyribonucleic acid-binding domain".J. Clin. Endocrinol. Metab.78 (2):313–6.doi:10.1210/jcem.78.2.8106618.PMID8106618.
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides".Gene.138 (1–2):171–4.doi:10.1016/0378-1119(94)90802-8.PMID8125298.
Yagi H, Ozono K, Miyake H, Nagashima K, Kuroume T, Pike JW (1993). "A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets".J. Clin. Endocrinol. Metab.76 (2):509–12.doi:10.1210/jcem.76.2.8381803.PMID8381803.
