VDR is expressed in most tissues of the body, and regulates transcription of genes involved in
intestinal and
renal transport of
calcium and other minerals.[8]Glucocorticoids decrease VDR expression.[8] Many types of immune cells also express VDR.[9]
Function
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 secondary
bile 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]
Clinical relevance
Mutations in this gene are associated with type II vitamin D-resistant
rickets. 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) and
sonic 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]
Interactions
Vitamin D receptor has been shown to
interact with many other factors which will affect transcription activation:
^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.
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^Abouzid M, Karazniewicz-Lada M, Glowka F (2018-10-19). "Genetic Determinants of Vitamin D-Related Disorders; Focus on Vitamin D Receptor". Current Drug Metabolism. 19 (12): 1042–1052.
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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.
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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.
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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.
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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.
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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.
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