The Vitamin D receptor (VDR), a nuclear hormone receptor for vitamin D3, is a protein that mediates the physiological actions of vitamin D by behaving as both a receptor for the vitamin, as well as a transcription factor for target genes. VDR is a member of the NR1I family, which also includes pregnane X (PXR) and constitutive androstane (CAR) receptors that form heterodimers with members of the retinoid X receptor family.
VDR principally regulates the expression of hormone sensitive genes that are involved in mineral metabolism. The specific ligand for the receptor is 1,25(OH)2D3, or vitamin D3. The liganded receptor heterodimerizes with the retinoid X receptor and recruits coactivators and corepressors. These coactivators include a chromatin remodeling complex called WINAC, which then interacts with acetylated histones. VDR also functions as a receptor for the secondary bile acid, lithocholic acid, and plays a crucial role in calcium homeostasis.
Downstream targets of this nuclear hormone receptor are principally involved in mineral metabolism though the receptor also regulates a variety of other metabolic pathways, such as those involved in the immune response and cell proliferation and differentiation (i.e., cancer). As a feedback inhibitory mechanism, VDRs repress expression of 1 alpha-hydroxylase, which is the proximal activator of D, and induce expression of the 1,25(OH)2D3 inactivating enzyme CYP24.
VDR has been identified as a bile acid receptor alongside FXR and function as protector of the gut against the toxic and carcinogenic effects of endobiotics. Mutations in the VDR gene are associated with type II vitamin D-resistant rickets, characterized by muscle weakness, growth retardation, bone deformity and secondary hyperparathyroidism.
Vitamin D receptor has been localized to chromosome 12q13.11, and spans approximately 102 kb and consists of 8 coding exons. The first three exons at the 5' end are non-coding. VDR belongs to the family of trans-acting transcriptional regulatory factors. It shows sequence similarity to the steroid and thyroid hormone receptors. The VDR protein is made of 427 amino acids and has a size of about 48 kDa. This protein is expressed mostly in the intestine, thyroid, and kidneys. The receptor is composed of two domains: a domain that binds to the hormone which is encoded by the first two coding exons, and a DNA binding domain containing two Zn2+-fingers, coded by the last three exons. Apart from these main domains, the protein also consists of a short N-terminal activation-function 1 (AF-1) domain, and a flexible "hinge" region that includes nuclear localization signals and an HSP-70 site.
More than 40 mutations have so far been identified in the VDR gene. Of the many polymorphisms reported in the VDR gene, three adjacent RFLPs for BsmI, ApaI, and TaqI have been studied most extensively and have been found to be associated with bone biology, renal diseases, and diabetes. All three of these polymorphisms are at the 3' end of the gene, and are likely to be non-functional.
Several mutations have been identified in the VDR gene causing type 2 vitamin D-resistant rickets. In addition, a single nucleotide polymorphism (SNP) has been identified in the initiation codon that results in an alternate translation start site three codons downstream. VDR gene has multiple transcript variants due to the alternative splicing resulting in different proteins.
In a Saudi Arabian child with vitamin D-resistant rickets type 2A with consanguineous parents, Lin et al. (1996) identified a G>A transition in exon 2 of the VDR gene, resulting in a gly46asp (p.G46D) substitution. Functional expression studies showed that the mutant receptor displayed normal binding affinity for 1,25-(OH)2D3, but had reduced affinity for DNA binding. The mutant VDR was unable to activate gene transcription in cells treated with up to 100 nmol/L of 1,25-(OH)2D3. Thus, this mutation, which occurs in the first zinc finger of the DNA-binding domain of the receptor, blocks 1,25-(OH)2D3 action.
Aljubeh et al. (2011) reported two unrelated patients with Familial Vitamin D Resistant Rickets. Both patients had the same novel missense p.R274H mutation in the VDR gene. Functional analysis of the mutation showed a 100-fold decrease in activity of the enzyme.
Osman et al. (2015) aimed to determine the frequency of the VDR SNPs rs731236 (Taq1) and rs2228570 (Fok1) in the Emirati population. DNA samples were collected from 282 healthy Emirati nationals and genotyping was carried out. It was found that the distribution of rs731236 (Taq1) and rs2228570 (Fok1) were AA 38%, AG 42%, GG 20% and AA 27%, AG 42%, GG 31% respectively. The authors noted that while the genotype and allele distribution did not differ from Caucasians in the United States and France, they showed a significant difference compared to Asian populations.
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