Human Vitamin D Receptor Mutations: Identification of Molecular Defects in Hypocalcemic Vitamin D Resistant Rickets
Our laboratories have been interested in the mechanism by which steroid receptors in general, and the 1,25-dihydroxyvitamin D (1,25(0H)2D) receptor specifically, interact with sequences in the target cell genome and regulate the transcription of specific gene products. Elucidation of these structure-function relationships of the l,25-(OH)2D3 receptor macromolecule have been hampered primarily because of its extremely low intracellular concentration (0.001%), even in primary target tissues such as intestine. This concentration is less than onetenth the cellular concentration of other steroid receptor molecules. Nonetheless, Pike and Haussler succeeded in purifying the chicken intestinal vitamin D receptor (1) and raised monoclonal antibodies which were reactive to both the chicken and mammalian isoforms (2). The monoclonals were used to recover vitamin D receptor (VDR) complementary DNA (cDNA) from a chicken intestine expression library (3). Subsequently, the chicken clones were used as probes to screen several human cDNA libraries and isolate the mammalian full length cDNA encoding the VDR (4). The nucleotide sequence of the 4605 base pair human cDNA was shown to include 1281 bp of open reading frame, 115 bp of noncoding leader sequence, and 3209 bp of 3′- noncoding sequence. The cloned sequence was subsequently transfected into COS-1 receptor negative monkey kidney cells and a single VDR species was produced that was indistinguishable from the native receptor (4).
KeywordsHormone Binding Thyroid Receptor Hormone Binding Domain Resistant Rickets Rickets Type
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- 7.F. Albright, A.M. Butler, E. Bloomberg, Rickets resistant to vitamin D therapy, Am J Dis Child 54:531 (1937).Google Scholar
- 8.D. Fraser, R.B. Salter, The diagnosis and management of the various types of rickets, Pediatr Clin N Am 5:417 (1958).Google Scholar
- 11.J.S. Adams, T.O. Wahl, W.V. Moore, W.A. Horton, B.P. Lukert, Familiar vitamin D-dependent rickets: further evidence for end organ resistance to active vitamin D metabolites. Program and Abstracts, 61st Annual Meeting of the Endocrine Society, 1979 767 (abstract).Google Scholar
- 16.S. Yoshikawa, T. Nakamura, Y. Nishii, Vitamin D dependent rickets with limited response to 1αOHD3 and high serum l,25-(OH)2D levels-long term follow-up, in: “Vitamin D: Chemical, Biochemical and Clinical Endocrinology of Calcium Metabolism”, A.W. Norman K. Schaefer, D.V. Herrath, H-G Grigoleit (eds.). Walter de Gruyter, New York (1982).Google Scholar
- 23.J.E. Griffin, J.S. Chandler, M.R. Haussler, J.E. Zerwekh, Receptor-positive resistance to 1,25 dihydroxyvitamin D3: a new cause of osteomalacia associated with impaired induction of 24-hydroxylase in fibroblasts, Clin Res 30:524A (1982).Google Scholar
- 24.T. Chen, Z. Hochberg, A. Benderli, S. Stanford, C. Cone, D. Feldman, Vitamin D-resistant rickets with alopecia: defective cytoplasmic receptors for l,25-(OH)2D3 in cultured skin fibroblasts, Abstracts at the Fourth Annual Meeting of the American Society for Bone and Mineral Research, S-49 (1982).Google Scholar
- 25.U.A. Lieberman, S. Balsan, S.J. Marx, True resistance to 1,25 dihydroxyvitamin D-cellular basis and implication of a new congenital syndrome, Abstracts of the 64th Meeting of the Endocrine Society (1982).Google Scholar
- 27.P.J. Malloy, Z. Hochberg, J.W. Pike, D. Feldman, Vitamin D dependent rickets, type II: vitamin D receptor analysis in cultured fibroblasts from patients and parents exhibiting normal steroid binding but decreased DNA binding, Clin Endocrinol and Metab (submitted).Google Scholar
- 31.T.L. Clements, J.S. Adams, N. Horiuchi, B.A. Cilchrest, H. Cho, Y. Tsuchiya, N. Matsuo, T. Suda, M.F. Holick, Interaction of 1,25 dihydroxyvitamin D3 with keratinocytes and fibroblasts from skin of normal subjects and a subject with vitamin D-dependent rickets, type II: a model for study of the mode of action of 1,25-dihydroxyvitamin D3, J. Clin Encodrinol Metab 56:824 (1983).CrossRefGoogle Scholar
- 36.J.S. Chandler, S.K. Chandler, J.W. Pike, M.R. Haussler, 1,25 dihy-droxyvitamin D3 induces 25-dihydroxyvitamin D3-24-hydroxylation in a cultured monkey kidney cell line (LLC-MK2) apparently deficient in the high affinity receptor for the hormone, J. Biol Chem 259:2214.Google Scholar
- 38.U.A. Lieberman, C. Eil, S.J. Marx, Receptor-positive hereditary resistance to 1,25-dihydroxyvitamin D: chromatography of hormone receptor complexes on deoxyribonucleic acid-cellulose shows two classes of mutation. J Clin Endocrinol Metab (1986).Google Scholar