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Hereditary 1,25-Dihydroxyvitamin D Resistant Rickets due to a Mutation Causing Multiple Defects in Vitamin D Receptor Function

Department of Medicine, Stanford University School of Medicine (P.J.M., R.X., L.P., D.F.), Stanford, California 94305; Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas, M. D. Anderson Cancer Center (S.P.), Houston, Texas 77030; and Department of Pediatrics, King Faisal Specialist Hospital and Research Center (A.A.-A.), Riyadh, Saudi Arabia

Address all correspondence and requests for reprints to: Dr. Peter J. Malloy, Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford University Medical Center, Room S025, Stanford, California 94305-5103. E-mail: malloy{at}cmgm.stanford.edu.

Hereditary vitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by mutations in the vitamin D receptor (VDR). We studied a young Saudi Arabian girl who exhibited the typical clinical features of HVDRR, but without alopecia. Analysis of her VDR gene revealed a homozygous T to C mutation in exon 7 that changed isoleucine to threonine at amino acid 268 (I268T). From crystallographic studies of the VDR ligand-binding domain, I268 directly interacts with 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] and is involved in the hydrophobic stabilization of helix H12. We recreated the I268T mutation and analyzed its effects on VDR function. In ligand binding assays, the I268T mutant VDR exhibited an approximately 5- to 10-fold lower affinity for [³H]1,25(OH)₂D₃ compared with the wild-type (WT) VDR. The I268T mutant required approximately a 65-fold higher concentration of 1,25(OH)₂D₃ to be equipotent in gene transactivation. Both retinoid X receptor heterodimerization and coactivator binding were reduced in the I268T mutant. Analogs of 1,25(OH)₂D₃ have been proposed as potential therapeutics for patients with HVDRR. Interestingly, in protease sensitivity assays, treatment with the potent vitamin D analog, 20-epi-1,25(OH)₂D₃, stabilized I268T mutant proteolytic fragments better than 1,25(OH)₂D₃. Moreover, 20-epi-1,25(OH)₂D₃ restored transactivation of the I268T mutant to levels exhibited by WT VDR treated with 1,25(OH)₂D₃. In conclusion, we describe a novel mutation, I268T, in the VDR ligand-binding domain that alters ligand binding, retinoid X receptor heterodimerization, and coactivator binding. These combined defects in VDR function cause resistance to 1,25(OH)₂D₃ action and result in the syndrome of HVDRR.

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