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Hereditary 1,25‐Dihydroxyvitamin D–Resistant Rickets Due to an Opal Mutation Causing Premature Termination of the Vitamin D Receptor
Author(s) -
Zhu Wenjing,
Malloy Peter J.,
Delvin Edgard,
Chabot Gilles,
Feldman David
Publication year - 1998
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.1998.13.2.259
Subject(s) - calcitriol receptor , rickets , medicine , endocrinology , microbiology and biotechnology , biology , stop codon , vitamin d and neurology , mutation , amino acid , genetics , gene
Mutations in the vitamin D receptor (VDR) gene have been shown to cause hereditary vitamin D–resistant rickets (HVDRR). The patient in this study is a young French‐Canadian boy with no known consanguinity in his family. The child exhibited the clinical characteristics of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated 1,25‐dihydroxyvitamin D (1,25(OH) 2 D) levels as well as total alopecia. Fibroblasts were cultured from a skin biopsy of the patient and used to assess the VDR. Northern blot analysis showed that a normal size VDR transcript was expressed; however, [ 3 H]1,25(OH) 2 D 3 ‐binding levels were very low and Western blot analysis failed to detect any VDR protein. Total resistance to 1,25(OH) 2 D 3 was demonstrated by the failure of the cultured fibroblasts to induce the transcription of the 25‐hydroxyvitamin D‐24‐hydroxylase gene when treated with high concentrations of 1,25(OH) 2 D 3 . Analysis of the DNA sequence revealed a unique C to T base change corresponding to nucleotide 218 of the VDR cDNA. This single base substitution changes the codon for arginine (CGA) to an opal stop codon (TGA), resulting in the truncation of the VDR at amino acid 30. The Arg30stop mutation prematurely terminates translation and deletes 398 amino acids including most of the zinc fingers as well as the entire ligand‐binding domain. Restriction fragment length polymorphism analysis of a Dde I restriction site created by the mutation showed that the parents were heterozygous for the mutant allele. In conclusion, the Arg30stop mutation truncates the VDR and leads to a hormone‐resistant condition which is the molecular basis of HVDRR in this patient.