PMID- 12403843 OWN - NLM STAT- MEDLINE DCOM- 20030618 LR - 20221207 IS - 0888-8809 (Print) IS - 0888-8809 (Linking) VI - 16 IP - 11 DP - 2002 Nov TI - 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. PG - 2538-46 AB - 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)(2)D(3)]. The patient did not have alopecia. Assays of the VDR showed a normal high affinity low capacity binding site for [(3)H]1,25-(OH)(2)D(3) 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)(2)D(3) 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)(2)D(3)-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. FAU - Malloy, Peter J AU - Malloy PJ AD - Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. FAU - Xu, Rong AU - Xu R FAU - Peng, Lihong AU - Peng L FAU - Clark, Pamela A AU - Clark PA FAU - Feldman, David AU - Feldman D LA - eng GR - DK-42482/DK/NIDDK NIH HHS/United States PT - Case Reports PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Mol Endocrinol JT - Molecular endocrinology (Baltimore, Md.) JID - 8801431 RN - 0 (RNA, Messenger) RN - 0 (Receptors, Calcitriol) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.- (Steroid Hydroxylases) RN - EC 1.14.15.16 (Vitamin D3 24-Hydroxylase) RN - FXC9231JVH (Calcitriol) SB - IM MH - Alopecia/genetics MH - Amino Acid Sequence MH - Amino Acid Substitution MH - Animals MH - Base Sequence MH - Binding Sites MH - COS Cells MH - Calcitriol/metabolism/pharmacology MH - Cesarean Section MH - Cytochrome P-450 Enzyme System/genetics MH - Genotype MH - Humans MH - Hypophosphatemia, Familial/*genetics MH - Infant, Newborn MH - Male MH - *Mutation MH - Polymorphism, Restriction Fragment Length MH - RNA, Messenger/genetics MH - Receptors, Calcitriol/chemistry/*genetics/*metabolism MH - Steroid Hydroxylases/genetics MH - Transcriptional Activation MH - United States MH - Vitamin D3 24-Hydroxylase MH - White People EDAT- 2002/10/31 04:00 MHDA- 2003/06/19 05:00 CRDT- 2002/10/31 04:00 PHST- 2002/10/31 04:00 [pubmed] PHST- 2003/06/19 05:00 [medline] PHST- 2002/10/31 04:00 [entrez] AID - 10.1210/me.2002-0152 [doi] PST - ppublish SO - Mol Endocrinol. 2002 Nov;16(11):2538-46. doi: 10.1210/me.2002-0152.