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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.

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