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

• Published in: The Journal of clinical investigation 1997-01, Vol.99 (2), p.297-304
• Main Authors: Malloy, P J, Eccleshall, T R, Gross, C, Van Maldergem, L, Bouillon, R, Feldman, D
• Format: Article
• Language: English
• Subjects: Calcitriol - metabolism; Calcitriol - therapeutic use; Child, Preschool; Dose-Response Relationship, Drug; Fibroblasts - cytology; Fibroblasts - metabolism; Heterozygote; Homozygote; Humans; Hypophosphatemia, Familial - genetics; Lipodystrophy; Male; Mullerian Ducts; Mutation; Polymorphism, Restriction Fragment Length; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Sequence Analysis, DNA; Syndrome; Transcriptional Activation; Turkey - ethnology; Vitamin D - metabolism
• ISSN: 0021-9738
• DOI: 10.1172/JCI119158

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.