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 D 3

Minh Nguyen, Arnold D'Alesio, Jean Marc Pascussi, Rajiv Kumar, Matthew D. Griffin, Xiangyang Dong, Huguette Guillozo, Marthe Rizk-Rabin, Christiane Sinding, Pierre Bougnères, Frédéric Jehan, Michèle Garabédian

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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)2D3-responsive gene, and relB, a critical NF-κB 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 childhood-onset type 1 diabetes. Mutations in the VDR ligand-binding domain may hamper the 1,25(OH)2D 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.

Original languageEnglish (US)
Pages (from-to)886-894
Number of pages9
JournalJournal of Bone and Mineral Research
Issue number6
StatePublished - Jun 1 2006



  • CYP24
  • Hereditary 1,25-dihydroxyvitamin D-resistant rickets
  • Type 1 diabetes
  • Vitamin D receptor mutations
  • relB

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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