title: Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness.
abstract: Mutations in the vitamin D receptor (VDR) result in target organ resistance to 1alpha,25-dihydroxyvitamin D [1,25(OH)2D3], the active form of vitamin D, and cause hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR). We analyzed the VDR of a patient who exhibited three genetic diseases: HVDRR, congenital total lipodystrophy, and persistent mullerian duct syndrome. The patient was treated with extremely high dose calcitriol (12.5 microg/d) which normalized serum calcium and improved his rickets. Analysis of [3H]1,25(OH)2D3 binding in the patient's cultured fibroblasts showed normal abundance of VDR with only a slight decrease in binding affinity compared to normal fibroblasts when measured at 0 degrees C. The patient's fibroblasts demonstrated 1,25(OH)2D3-induction of 24-hydroxylase mRNA, but the effective dose was approximately fivefold higher than in control cells. Sequence analysis of the patient's VDR gene uncovered a single point mutation, H305Q. The recreated mutant VDR was transfected into COS-7 cells where it was 5 to 10-fold less responsive to 1,25(OH)2D3 in gene transactivation. The mutant VDR had an eightfold lower affinity for [3H]1,25(OH)2D3 than the normal VDR when measured at 24 degrees C. RFLP demonstrated that the patient was homozygous for the mutation while the parents were heterozygous. In conclusion, we describe a new ligand binding domain mutation in the VDR that causes HVDRR due to decreased affinity for 1,25(OH)2D3 which can be effectively treated with extremely high doses of hormone.
authors.affiliation: Stanford University, California 94305, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Malloy
authors.forename: T R
authors.initials: TR
authors.lastname: Eccleshall
authors.forename: C
authors.initials: C
authors.lastname: Gross
authors.forename: L
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
authors.forename: D
authors.initials: D
authors.lastname: Feldman
mesh_terms: D002117:Calcitriol / Q000378:metabolism / Q000627:therapeutic use; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics*; D008060:Lipodystrophy; D008297:Male; D009095:Mullerian Ducts; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D013577:Syndrome; D015533:Transcriptional Activation; D014421:Turkey / Q000208:ethnology; D014807:Vitamin D / Q000378:metabolism*
chemical_list: D018167:Receptors, Calcitriol; D014807:Vitamin D; D002117:Calcitriol