Tryptophan Missense Mutation in the Ligand-Binding Domain of the Vitamin D Receptor Causes Severe Resistance to 1,25-Dihydroxyvitamin D
| Autor: | H. Guillozo, C. Palix, T. M. Nguyen, Marthe Rizk-Rabin, F. Brouillard, P. Lagier, M. L. Kottler, J.M. Garnier, Michèle Garabédian, P. Adiceam |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
Vitamin medicine.medical_specialty DNA Complementary Endocrinology Diabetes and Metabolism Mutation Missense Rickets Biology Ligands Transfection Calcitriol receptor chemistry.chemical_compound Transactivation Calcitriol Cytochrome P-450 Enzyme System Internal medicine medicine Vitamin D and neurology Animals Humans Orthopedics and Sports Medicine Amino Acid Sequence RNA Messenger Vitamin D3 24-Hydroxylase Receptor Cells Cultured Hypophosphatemia Familial Binding Sites Base Sequence Tryptophan Infant Ligand (biochemistry) medicine.disease Recombinant Proteins Endocrinology chemistry Child Preschool COS Cells Steroid Hydroxylases Receptors Calcitriol Female Hair Follicle |
| Zdroj: | Journal of Bone and Mineral Research. 17:1728-1737 |
| ISSN: | 0884-0431 |
| Popis: | In this study, two related young children, brother and sister, exhibited severe vitamin D-resistant rickets without alopecia. Sequence analysis of the total vitamin D receptor (VDR) cDNA from skin fibroblasts revealed a substitution of the unique tryptophan of the VDR by arginine at amino acid 286 (W286R). Cultured skin fibroblasts of the two patients expressed normal-size VDR protein (immunocytochemistry and Western blotting) and normal length VDR mRNA (Northern blotting). But, these fibroblasts, as well as COS-7 cells transfected with the W286R mutant, failed to bind 3H 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The tryptophan substitution did not affect VDR trafficking toward the nucleus but abolished the 24-hydroxylase gene response to 1,25(OH)2D3, even at 10(-6) M concentrations. In conclusion, this case report of a new family with hereditary vitamin D-resistant rickets (HVDRR) emphasizes the crucial role of the VDR tryptophan for ligand binding and for transactivation of 1,25(OH)2D3 target genes. It clearly shows the clinical significance of this VDR amino acid for calcium homeostasis and bone mineralization. This observation suggests further that the presence of a stable VDR-bound ligand may not be obligatory for normal hair follicle development. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text