Vitamin D resistance and alopecia: a kindred with normal 1,25-dihydroxyvitamin D binding, but decreased receptor affinity for deoxyribonucleic acid.

M A Hirst; H I Hochman; D Feldman

doi:10.1210/jcem-60-3-490

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Vitamin D resistance and alopecia: a kindred with normal 1,25-dihydroxyvitamin D binding, but decreased receptor affinity for deoxyribonucleic acid.

M A Hirst·H I Hochman·D Feldman

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Abstract

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.

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Adolescent Adult Alopecia Cells, Cultured Cytochrome P-450 Enzyme System DNA Female Fibroblasts Humans Hypophosphatemia, Familial Male Receptors, Calcitriol Receptors, Steroid Steroid Hydroxylases Vitamin D3 24-Hydroxylase Journal Article Research Support, U.S. Gov't, P.H.S.

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M A Hirst, H I Hochman, D Feldman. 1985. Vitamin D resistance and alopecia: a kindred with normal 1,25-dihydroxyvitamin D binding, but decreased receptor affinity for deoxyribonucleic acid.. https://doi.org/10.1210/jcem-60-3-490

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