M. Hewison et al., TISSUE RESISTANCE TO 1,25-DIHYDROXYVITAMIN-D WITHOUT A MUTATION OF THE VITAMIN-D RECEPTOR GENE, Clinical endocrinology, 39(6), 1993, pp. 663-670
OBJECTIVE Hereditary vitamin D resistant rickets (HVDRR) is characteri
zed by severe rickets and is often accompanied by alopecia. Mutations
in the gene encoding the vitamin D receptor have been found in this co
ndition. In a patient with the characteristic phenotype we have invest
igated the functional defect and sequenced the gene to seek a mutation
. DESIGN Patient and control cell lines prepared from skin fibroblasts
and peripheral brood lymphocytes were used to measure binding of 1,25
(OH)(2)D-3 and to isolate vitamin D receptor mRNA. VDR cDNA was sequen
ced and transfected into receptor defective cells. PATIENT A child wit
h alopecia diagnosed as having rickets due to resistance to 1,25(OH)(2
)D-3. MEASUREMENTS Cytosolic binding and nuclear association of 1,25(O
H)(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 a
ctivity. VDR mRNA was prepared, reverse transcribed, and cDNA sequence
d. VDR cDNA was also transfected into VDR-deficient CV-1 cells and fun
ctional 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 nuclea
r 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 transactivation in the presence of 1,25(OH)(2)
D-3. CONCLUSION These data indicate a new cause of tissue resistance t
o 1,25(OH)(2)D-3 which occurs in the absence of mutations in the codin
g region of VDR gene and which is characterized by defective nuclear l
ocalization of this receptor.