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Tissue resistance to 1,25‐dihydroxyvitamin D without a mutation of the vitamin D receptor gene
Author(s) -
Hewison M.,
Rut A. R.,
Kristjansson K.,
Walker R. E.,
Dillon M. J.,
Hughes M. R.,
O'Riordan J. L. H.
Publication year - 1993
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.1993.tb02424.x
Subject(s) - calcitriol receptor , transfection , endocrinology , medicine , rickets , microbiology and biotechnology , vitamin d and neurology , biology , complementary dna , receptor , reporter gene , gene , gene expression , genetics
Summary OBJECTIVE Hereditary vitamin D resistant rickets (HVDRR) is characterized by severe rickets and is often accompanied by alopecia. Mutations in the gene encoding the vitamin D receptor have been found in this condition. In a patient with the characteristic phenotype we have investigated the functional defect and sequenced the gene to seek a mutation. DESIGN Patient and control cell lines prepared from skin fibroblasts and peripheral blood lymphocytes were used to measure binding of 1,25(OH) 2 D 3 and to isolate vitamin D receptor mRNA. VDR cDNA was sequenced and transfected into receptor defective cells. PATIENT A child with alopecia diagnosed as having rickets due to resistance to 1,25(OH) 2 D 3 . MEASUREMENTS Cytosolic binding and nuclear association of 1,25(OH) 2 D 3 were determined in patient and control cells, and functional response to 1,25(OH) 2 D 3 assessed by measurement of 24‐hydroxylase activity. VDR mRNA was prepared, reverse transcribed, and cDNA sequenced. VDR cDNA was also transfected into VDR‐deficient CV‐1 cells and functional response to 1,25(OH) 2 D 3 assessed by co‐transfection with a chloramphenicol acetyltransferase (CAT) reporter plasmid. RESULTS VDR from the patient were able to bind 1,25(OH) 2 D 3 but showed no nuclear localization resulting in an absence of functional response to 1,25(OH) 2 D 3 . Sequencing revealed that the VDR coding region was normal. Expression studies of the patient's VDR showed functionally normal VDR as evidenced by normal trans‐activation in the presence of 1,25(OH) 2 D 3 . CONCLUSION These data indicate a new cause of tissue resistance to 1,25(OH) 2 D 3 which occurs in the absence of mutations in the coding region of VDR gene and which is characterized by defective nuclear localization of this receptor.