Vitamin D–Resistant Rickets and Type 1 Diabetes in a Child With Compound Heterozygous Mutations of the Vitamin D Receptor (L263R and R391S): Dissociated Responses of the CYP-24 and rel-B Promoters to 1,25-Dihydroxyvitamin D3

Abstract

We report here the first association between vitamin D-resistant rickets, alopecia, and type 1 diabetes in a child with compound heterozygous mutations in the VDR gene. Transfection studies suggest dissociated effects of VDR gene mutations on the regulation of genes involved in vitamin D metabolism and dendritic cell maturation.Introduction: Whereas vitamin D may play a role in the immune tolerance process, no patient has been reported to associate hereditary vitamin D-resistant rickets (HVDRR) and an autoimmune disease, and no attempt has been made to delineate the outcome of mutations of the vitamin D receptor (VDR) on the transcription of genes controlling immune tolerance. Materials and Methods:The VDR gene was analyzed in a child with vitamin D-resistant rickets, total alopecia, and early childhood-onset type 1 diabetes. Patient's fibroblasts and COS-7 cells transfected with wildtype or mutant VDRs were studied for ligand-binding capacity, transactivation activity using two gene promoters [CYP-24, a classical 1,25(OH) 2 D 3 -responsive gene, and relB, a critical NF-B component for regulation of dendritic cell differentiation], VDR-RXR heterodimers association to CYP 24 VDREs by gel mobility shift assays, and co-activator binding by Glutathione-S-transferase pull-down assays. Results: Two novel compound heterozygous mutations (L263R and R391S) were identified in the VDR ligand-binding domain in this child. Both mutations significantly impaired VDR ligand-binding capacity but had dissociated effects on CYP-24 and RelB promoter responses to vitamin D. CYP 24 response binding to SRC-1 and RXR-heterodimer binding to CYP24 VDREs were abolished in L263R mutants but normal or partially altered in R391S mutants. In the opposite, RelB responses to vitamin D were close to normal in L263R mutants but abolished in R391S mutants. Conclusions:We report the first clinical association between HVDRR, total alopecia, and early childhoodonset type 1 diabetes. Mutations in the VDR ligand-binding domain may hamper the 1,25(OH) 2 D 3 -mediated relB responses, an effect that depends on the site of the VDR mutation and cannot be anticipated from VDR ligand-binding ability or CYP-24 response. Based on these results, we propose to survey the immune function in patients with HVDRR, including those with moderate features of rickets.

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

“…The importance of this residue on the dimerization process with retinoid X receptor alpha (RXRA) was previously shown with an artificial p.Arg415Ala mutant, which resulted in a complete loss of function (Shulman et al, 2004). In addition, this position is homologous to p.Arg391Cys/Ser mutations in vitamin D receptor (VDR) (Figure 2), which have been shown to cause vitamin D-resistant rickets by destabilizing the dimerization with RXRA (Nguyen et al, 2006;Whitfield et al, 1996). To evaluate whether the LXRA p.Arg415Gln mutation has a similar detrimental effect on the dimerization with RXRA, we performed binding assays with wildtype and mutant LXRA.…”

Compound Heterozygous Mutations in the Vitamin D Receptor in a Patient With Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets With Alopecia

“…(14,15) In addition to this case, two other cases of HVDRR were shown to be caused by compound heterozygous mutations in the VDR. (4,16) Both patients also had alopecia. One patient had two missense mutations in the VDR LBD that resulted in L263R and R391S amino acid substitutions.…”

“…One patient had two missense mutations in the VDR LBD that resulted in L263R and R391S amino acid substitutions. (16) The second patient had a single base deletion in exon 4 that led to a frameshift and downstream termination codon in exon 4 and a missense mutation in the VDR LBD that resulted in an E329K amino acid substitution. (4) The clinical case had some slightly unusual features.…”

Identification of a Novel Nonsense Mutation in the Ligand-Binding Domain of the Vitamin D Receptor Gene and Clinical Description of Two Greek Patients with Hereditary Vitamin D-Resistant Rickets and Alopecia

“…Indeed, functional analyses of mutated VDR LBD have shown that defects in this protein region may affect adequate protein expression, the heterodimerization process or the VDR affinity to ligand or coactivators. Alopecia has been suggested to be associated with mutations in LBD subregions which are essential for the heterodimerization with RXR [7,18,21,22,23] and is generally related to severe hormone resistance [1]. Furthermore, treatments may correct the serum biochemical profile and heal the rickets, with no significant change in the hair development.…”