Deletion of DNA Binding Domain of the Vitamin D Receptor Abrogates Genomic and Nongenomic Functions of Vitamin D

The study generated vitamin D receptor (VDR) null mutant mice with a VDR lacking the DNA binding domain but retaining the hormone binding domain. These mice exhibited widespread lacZ expression and phenocopied VDR protein-lacking mice, showing growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Despite dietary normalization of blood calcium and serum PTH levels, a renal calcium leak persisted. Pharmacological doses of vitamin D metabolites failed to elicit responses in key tissues, indicating the mutant receptor's nonfunctionality and the minor role of non-classical vitamin D signaling pathways. Additionally, rapid nongenomic responses in osteoblasts were absent, confirming the classical VDR's role in these actions.