This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cockerill, F. J. Articles by Farrow, S. M. Search for Related Content PubMed PubMed Citation Articles by Cockerill, F. J. Articles by Farrow, S. M.

Mutations in the Vitamin D Receptor Gene in Three Kindreds Associated with Hereditary Vitamin D Resistant Rickets

Department of Medicine, University College London Medical School, Middlesex Hospital, London W1N 8AA, United Kingdom

Address correspondence and reprint requests to: Dr. S. M. Farrow, Department of Medicine, University College London Medical School, Middlesex Hospital, Mortimer Street, London, United Kingdom W1N 8AA. e-mail: s.farrow@ucl.ac.uk

Abstract

Hereditary vitamin D resistant rickets has been associated with a number of mutations within the DNA and ligand binding domains of vitamin D receptors (VDR). The aim of our study was to identify and characterize the causative mutations in three kindreds with this condition.

Resistance to 1,25(OH)₂D₃ was confirmed in cultured skin fibroblasts in which there was no induction of 24-hydroxylase activity; binding of 1,25(OH)₂D₃ to VDR was undetectable in patients 1 and 2, but normal in patients 3 and 4. The coding region of the VDR gene was sequenced to seek mutations. A mutation in the VDR gene of patient 1 resulted in a STOP codon, patient 2 showed a 56 bp deletion leading to frameshift and premature termination of VDR; a point mutation of A to C lying within the hormone-binding domain was shown for patients 3 and 4, who were siblings. Transactivation studies confirmed that these were functional mutations. Gel shift assays using nuclear extract from patient 3 demonstrated that the mutation that altered a conserved amino acid (glutamine-259) known to be involved in heterodimerization with other nuclear receptors affected protein:protein interactions.

This article has been cited by other articles:

				Y. Fang, J. B. J. van Meurs, F. Rivadeneira, N. M. van Schoor, J. P. T. van Leeuwen, P. Lips, H. A. P. Pols, and A. G. Uitterlinden Vitamin D Receptor Gene Haplotype Is Associated with Body Height and Bone Size J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1491 - 1501. [Abstract] [Full Text] [PDF]

				P. J. Malloy, R. Xu, L. Peng, S. Peleg, A. Al-Ashwal, and D. Feldman Hereditary 1,25-Dihydroxyvitamin D Resistant Rickets due to a Mutation Causing Multiple Defects in Vitamin D Receptor Function Endocrinology, November 1, 2004; 145(11): 5106 - 5114. [Abstract] [Full Text] [PDF]

				P. J. Malloy, J. W. Pike, and D. Feldman The Vitamin D Receptor and the Syndrome of Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets Endocr. Rev., April 1, 1999; 20(2): 156 - 188. [Abstract] [Full Text]