ABSTRACT
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.
Subject(s)
Calcitriol/pharmacology , Hypophosphatemia, Familial/genetics , Receptors, Calcitriol/drug effects , Receptors, Calcitriol/genetics , Amino Acid Sequence , Animals , Base Sequence , Binding Sites/genetics , COS Cells , Cells, Cultured , Child, Preschool , Cytochrome P-450 Enzyme System/genetics , DNA, Complementary/genetics , Female , Hair Follicle/growth & development , Humans , Infant , Ligands , Male , Mutation, Missense , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Calcitriol/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Steroid Hydroxylases/genetics , Transfection , Tryptophan/genetics , Vitamin D3 24-HydroxylaseABSTRACT
We report on a case of fetal goitrous diagnosed on ultrasonogram done at 31 weeks of gestation. Thyroid maternal function was normal and no therapeutic was responsible. Hormonal test done on cord blood supported diagnosis of prenatal hypothyroidism. The infant was born prematurely at gestation age of 34 without antenatal treatment. He was eutrophic with clinical and biological signs of hypothyroidism and a large goiter. Therapy with thyroxine was instituted on the third day of life. At 9 months, growth and development are normal. Congenital hypothyroidism has an incidence of approximately 1 in every 4000-5000 live births. Rarely fetal goitrous hypothyroidism have been attributed to thyroid hormone dyshormonogenesis. When fetal goiter is diagnosed on ultrasonography, without maternal hypothyroidism or therapeutic and when hypothyroidism is confirmed on fetal blood, this diagnosis must be suspected.