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Tryptophan Missense Mutation in the Ligand‐Binding Domain of the Vitamin D Receptor Causes Severe Resistance to 1,25‐Dihydroxyvitamin D
Author(s) -
Nguyen T. M.,
Adiceam P.,
Kottler M. L.,
Guillozo H.,
RizkRabin M.,
Brouillard F.,
Lagier P.,
Palix C.,
Garnier J. M.,
Garabedian M.
Publication year - 2002
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2002.17.9.1728
Subject(s) - calcitriol receptor , endocrinology , medicine , rickets , transactivation , missense mutation , receptor , biology , vitamin d and neurology , vitamin , chemistry , microbiology and biotechnology , mutation , biochemistry , transcription factor , gene
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 D 3 [1,25(OH) 2 D 3 ]. The tryptophan substitution did not affect VDR trafficking toward the nucleus but abolished the 24‐hydroxylase gene response to 1,25(OH) 2 D 3 , 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) 2 D 3 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.