Hereditary 1,25-dihydroxyvitamin D resistant rickets due to a mutation causing multiple defects in vitamin D receptor function.
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 D(3) [1,25(OH)(2)D(3)] 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 [(3)H]1,25(OH)(2)D(3) compared with the wild-type (WT) VDR. The I268T mutant required approximately a 65-fold higher concentration of 1,25(OH)(2)D(3) 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)(2)D(3) 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)(2)D(3), stabilized I268T mutant proteolytic fragments better than 1,25(OH)(2)D(3). Moreover, 20-epi-1,25(OH)(2)D(3) restored transactivation of the I268T mutant to levels exhibited by WT VDR treated with 1,25(OH)(2)D(3). 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)(2)D(3) action and result in the syndrome of HVDRR.
Malloy
Peter J
PJ
Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford University Medical Center, Room S025, Stanford, California 94305-5103, USA. malloy@cmgm.stanford.edu
Xu
Rong
R
Peng
Lihong
L
Peleg
Sara
S
Al-Ashwal
Abdullah
A
Feldman
David
D
D000505:Alopecia; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002117:Calcitriol / Q000627:therapeutic use*; D002120:Calcium Channel Agonists / Q000627:therapeutic use*; D019281:Dimerization; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D010447:Peptide Hydrolases / Q000494:pharmacology; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000737:chemistry / Q000378:metabolism; D012279:Rickets / Q000188:drug therapy* / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects
D002120:Calcium Channel Agonists; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D010447:Peptide Hydrolases; D002117:Calcitriol