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. (original) (raw)

Research Article Free access | 10.1172/JCI119158

T R Eccleshall, C Gross, L Van Maldergem, R Bouillon, and D Feldman

Stanford University, California 94305, USA.

Find articles by Malloy, P. in:[JCI](/search/results?q=author.first%5Fname%3A%22P J%22+author.last%5Fname%3A%22Malloy%22&search%5Ftype=advanced) |PubMed |Google Scholar

Stanford University, California 94305, USA.

Find articles by Eccleshall, T. in:[JCI](/search/results?q=author.first%5Fname%3A%22T R%22+author.last%5Fname%3A%22Eccleshall%22&search%5Ftype=advanced) |PubMed |Google Scholar

Stanford University, California 94305, USA.

Find articles by Gross, C. in:JCI |PubMed |Google Scholar

Stanford University, California 94305, USA.

Find articles by Van Maldergem, L. in:[JCI](/search/results?q=author.first%5Fname%3A%22L%22+author.last%5Fname%3A%22Van Maldergem%22&search%5Ftype=advanced) |PubMed |Google Scholar

Stanford University, California 94305, USA.

Find articles by Bouillon, R. in:JCI |PubMed |Google Scholar

Stanford University, California 94305, USA.

Find articles by Feldman, D. in:JCI |PubMed |Google Scholar

Published January 15, 1997 -More info

Published January 15, 1997 -Version history

View PDF

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.

Version history