title: 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.
  
  
  BACKGROUND
  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.
  
  
  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-kappaB 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)2D3-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.
authors.affiliation: INSERM Unité 561, Hôpital St Vincent de Paul, Paris, France. thai-nguyen@paris5.inserm.fr
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.forename: Arnold
authors.initials: A
authors.lastname: d'Alesio
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Griffin
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Dong
authors.forename: Huguette
authors.initials: H
authors.lastname: Guillozo
authors.forename: Marthe
authors.initials: M
authors.lastname: Rizk-Rabin
authors.forename: Christiane
authors.initials: C
authors.lastname: Sinding
authors.forename: Pierre
authors.initials: P
authors.lastname: Bougnères
authors.forename: Frédéric
authors.initials: F
authors.lastname: Jehan
authors.forename: Michèle
authors.initials: M
authors.lastname: Garabédian
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D005602:France; D005784:Gene Amplification; D016678:Genome; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000150:complications* / Q000235:genetics; D008297:Male; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013250:Steroid Hydroxylases / Q000235:genetics*; D051841:Transcription Factor RelB / Q000235:genetics*; D065668:Vitamin D3 24-Hydroxylase; D044465:White People / Q000235:genetics
chemical_list: C497593:RELB protein, human; D018167:Receptors, Calcitriol; D051841:Transcription Factor RelB; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol