Vitamin D resistance and alopecia: a kindred with normal 1,25-dihydroxyvitamin D binding, but decreased receptor affinity for deoxyribonucleic acid.
A new kindred exhibiting vitamin D resistance and alopecia is described. Clinically, three of seven sisters demonstrated rickets, hypocalcemia, elevated serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] levels, and alopecia. Biochemical analysis of cultured fibroblasts from skin biopsy explants in two affected and one normal sister revealed normal [3H]1,25-(OH)2D3 binding to receptors (Kd = 0.05 nM; Nmax = 30-50 fmol/mg protein). Despite normal steroid binding, cells from the two affected sisters failed to respond to 1,25-(OH)2D3 in vitro, as measured by induction of the enzyme 25-hydroxyvitamin D-24-hydroxylase. The cells from the normal sister showed a response within the range of five normal cell lines. Sucrose gradient analysis yielded a typical 3.2S protein under high salt conditions in extracts from the three siblings, but with reduced capacity to aggregate to a 6S moiety in low salt gradients in the two affected cells. Whole cell [3H]1,25-(OH)2D3 binding studies revealed nearly normal localization of bound receptor to the nuclear compartment. Elution of bound receptors by KCl gradients from both DNA-cellulose or fibroblast nuclei demonstrated that the receptors from the affected sisters exhibited decreased affinity for DNA compared to those from normal subjects. We conclude that 1,25-(OH)2D3 receptors from these resistant fibroblasts have a normal steroid-binding domain, but a defective nuclear binding domain. We believe that this abnormality may be responsible for the vitamin D resistance observed both in vivo and in vitro.
Hirst
M A
MA
Hochman
H I
HI
Feldman
D
D
D000293:Adolescent; D000328:Adult; D000505:Alopecia / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System; D004247:DNA / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000235:genetics / Q000378:metabolism*; D008297:Male; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase