Vitamin D receptor (VDR) H305Y mutant (VDR (H305Y))

The Human Vitamin D receptor (VDR) mutant H305Y is a pathological variant of the VDR, a nuclear receptor that serves as the primary mediator for the biological actions of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol) (UniProt: P11473). As a ligand-activated transcription factor, the VDR is essential for maintaining systemic calcium and phosphate levels and ensuring proper bone mineralization (PubMed: 24336193). The H305 residue, located within the ligand-binding domain, plays a critical role in anchoring the ligand via a hydrogen bond to its 25-hydroxyl group; the H305Y mutation replaces this histidine with tyrosine, significantly reducing the receptor's affinity for calcitriol (PubMed: 11108268). This molecular defect results in Hereditary Vitamin D-Resistant Rickets (HVDRR), a condition characterized by severe rickets, hypocalcemia, and secondary hyperparathyroidism despite elevated levels of circulating calcitriol (OMIM: 277440). Patients with this mutation often exhibit resistance to standard vitamin D supplementation, necessitating aggressive therapeutic interventions such as extremely high doses of calcitriol or long-term intravenous calcium infusions to bypass the receptor's signaling deficit (PubMed: 15769993). Beyond mineral metabolism, the VDR is also involved in immune modulation and cell proliferation, meaning mutations like H305Y can have broad physiological implications.

Other names

NR1I1 H305Y1,25-dihydroxyvitamin D3 receptor H305YNuclear receptor subfamily 1 group I member 1 H305YVitamin D3 receptor H305Y

The VDR H305Y mutant acts as a dysfunctional ligand-activated transcription factor. In its wild-type form, VDR binds its active ligand, calcitriol, heterodimerizes with the Retinoid X Receptor (RXR), and binds to Vitamin D Response Elements (VDREs) in the DNA to regulate gene expression (PubMed: 12144494). The H305Y mutation occurs in the ligand-binding domain and disrupts the critical hydrogen bond normally formed between the histidine residue and the 25-hydroxyl group of calcitriol (PubMed: 11108268). This disruption significantly reduces the receptor's affinity for the ligand and impairs the recruitment of coactivators, leading to a failure in the transactivation of genes necessary for mineral metabolism.