A Novel Mutation in Helix 12 of the Vitamin D Receptor Impairs Coactivator Interaction and Causes Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets without Alopecia

Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum co...

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Published in:Molecular endocrinology (Baltimore, Md.) Md.), 2002-11, Vol.16 (11), p.2538-2546
Main Authors: Malloy, Peter J, Xu, Rong, Peng, Lihong, Clark, Pamela A, Feldman, David
Format: Article
Language:English
Subjects:
Alopecia - genetics
Amino Acid Sequence
Amino Acid Substitution
Animals
Base Sequence
Binding Sites
Calcitriol - metabolism
Calcitriol - pharmacology
Cesarean Section
COS Cells
Cytochrome P-450 Enzyme System - genetics
European Continental Ancestry Group
Genotype
Humans
Hypophosphatemia, Familial - genetics
Infant, Newborn
Male
Mutation
Polymorphism, Restriction Fragment Length
Receptors, Calcitriol - chemistry
Receptors, Calcitriol - genetics
Receptors, Calcitriol - metabolism
RNA, Messenger - genetics
Steroid Hydroxylases - genetics
steroid receptor coactivator 1
Transcriptional Activation
United States
vitamin D 24-hydroxylase
vitamin D receptor-interacting protein
Vitamin D3 24-Hydroxylase
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Summary:Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). The patient in this study exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25-(OH)2D3]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [3H]1,25-(OH)2D3 in extracts from the patient’s fibroblasts. However, the cells were resistant to 1,25-dihydroxyvitamin D action as demonstrated by the failure of the patient’s cultured fibroblasts to induce the 24-hydroxylase gene when treated with either high doses of 1,25-(OH)2D3 or vitamin D analogs. A novel point mutation was identified in helix H12 in the ligand-binding domain of the VDR that changed a highly conserved glutamic acid at amino acid 420 to lysine (E420K). The patient was homozygous for the mutation. The E420K mutant receptor recreated by site-directed mutagenesis exhibited many normal properties including ligand binding, heterodimerization with the retinoid X receptor, and binding to vitamin D response elements. However, the mutant VDR was unable to elicit 1,25-(OH)2D3-dependent transactivation. Subsequent studies demonstrated that the mutant VDR had a marked impairment in binding steroid receptor coactivator 1 (SRC-1) and DRIP205, a subunit of the vitamin D receptor-interacting protein (DRIP) coactivator complex. Taken together, our data indicate that the mutation in helix H12 alters the coactivator binding site preventing coactivator binding and transactivation. In conclusion, we have identified the first case of a naturally occurring mutation in the VDR (E420K) that disrupts coactivator binding to the VDR and causes HVDRR.
ISSN:0888-8809
1944-9917
DOI:10.1210/me.2002-0152