Functional analyses of a novel missense and other mutations of the vitamin D receptor in association with alopecia

Abstract

Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a rare disorder, caused by bialellic mutations of the vitamin D receptor (VDR) gene, sometimes associated with alopecia. The aim of this study is to elucidate the mechanism of functional disruption of a novel mutation, detected in a patient with HVDRR, comparing to other mutations with or without alopecia. The patient was a 2-year-old girl with alopecia, who was clinically diagnosed as HVDRR. Genetic analysis revealed a novel homozygous mutation, S360P, located in ligand binding domain (LBD). The mutation was predicted as not disease causing by Polyphen2 and SIFT. But the transcriptional activity of S360P was disrupted as well as other reported mutations, Q152X (located in the hinge lesion), and R274L, H305Q (located in LBD). Following assays revealed no ligand binding affinity, no interaction with cofactors or RXR and no functioning of nuclear localization signals. Our results provide an additional evidence for the previous findings suggesting that DNA binding by the VDR/RXR heterodimer is essential for the function of the VDR in hair development. In conclusion, we identified a novel missense mutation of VDR causing HVDRR with alopecia. Functional analyses revealed that the single amino acid substitution could disrupt the function of the protein.

Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?

“…[203][204][205][206] VD binds the vitamin D receptor (VDR) for signal transduction and interacts with other factors, such as the vitamin D-binding protein, retinoid X receptor, and peroxisome proliferator-activated receptor (PPAR). 170,171,207,208 Previous studies have shown that the Th-2 cell response plays an important role in the pathogenesis of T1DM and AITD, [209][210][211][212] whereas VD supplementation reverses the inappropriate activation of T cells and improves immune homeostasis, suggesting a therapeutic value for VD in concurrent autoimmune diseases. 145,189,211 VDR is critical for the correct biological function of VD in several processes such as the modulation of calcium homeostasis and bone growth.…”

Coordination among frequent genetic variants imparts substance use susceptibility and pathogenesis

“…Since altered circadian behavior is known to be a significant risk contributor toward the development of SUDs, qualifying NCOR1 as an excellent candidate for further investigations in the context of SUDs. Further, NCOR1 also exhibits ligand-dependent interaction with vitamin D receptor (VDR) ( Tamura et al, 2017 ); our pathway analysis further revealed VDR to regulate EDN1, an important regulator of immediate early response genes of substance use such as, MYC, FOSL1 and FOSB, in addition to regulating key neuropeptides, adrenomedullin (ADM), and natriuretic peptide B (NPPB). The downstream relationship of NCOR1 to known SUDs influencing dopaminergic activators suggests a potential role in increasing susceptibility to substance use, necessitating further research.…”

Genes and Eating Preferences, Their Roles in Personalized Nutrition

“…The rs1544410 polymorphism ( Figure 22) reduces receptor sensitivity to vitamin D, and, therefore, there is an increase in the calcium removal from bones. As a result, there is a decrease in the mineral bone density, and the risk of osteoporosis increases [59]. The GC gene encodes the vitamin D binding protein; its rs2282679 polymorphism ( Figure 23) is associated with a change in the level of vitamin D in the blood [60].…”