Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets
Fatima A. H. Al-Jaberi, Martin Kongsbak‐Wismann, Alejandro Aguayo‐Orozco, Nicolai Krogh, Terkild B. Buus, Daniel Villalba Lopez, Anna K. O. Rode, Eva Gravesen, Klaus Ølgaard, Søren Brunak, Anders Woetmann, Niels Ødum, Charlotte M. Bonefeld, Carsten Geisler
Abstract
The active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH) 2 D 3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH) 2 D 3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH) 2 D 3 -induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH) 2 D 3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH) 2 D 3 -induced translocation of the VDR to the nucleus and 1,25(OH) 2 D 3 -induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.