文章基本信息

标题：An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families
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作者：H H Ritchie ; M R Hughes ; E T Thompson 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1989
卷号：86
期号：24
页码：9783-9787
DOI：10.1073/pnas.86.24.9783
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Hereditary 1,25-dihydroxyvitamin D3-resistant rickets is a rare autosomal-recessive disease resulting from target-organ resistance to the action of the active hormonal form of vitamin D. Four affected children from three related families with the classical syndrome of hereditary 1,25-dihydroxyvitamin D3-resistant rickets and the absence of detectable binding to the vitamin D receptor (VDR) in cultured fibroblasts or lymphoblasts were examined for genetic abnormalities in the VDR gene. Genomic DNA from Epstein-Barr virus-transformed lymphoblasts of eight family members was isolated and amplified by polymerase chain reaction techniques. Amplified fragments containing the eight structural exons encoding the VDR protein were sequenced. The DNA from all affected children exhibited a single C----A base substitution within exon 7 at nucleotide 970 that resulted in the conversion of the normal codon for tyrosine (TAC) into a premature termination codon (TAA) at amino acid 292. This mutation causes a truncation of the VDR protein thereby deleting a large portion of the steroid hormone binding domain (amino acids 292-424). Although the affected children were all homozygotic for the mutation, the four parents tested all exhibited both wild-type and mutant alleles, indicating a heterozygous state. The functional consequences of this mutation were confirmed after expression of the recreated mutant VDR cDNA in mammalian cells. Recreated mutant receptor exhibited no specific 1,25-[3H]dihydroxyvitamin D3 binding and failed to activate a cotransfected VDR promoter-reporter gene construct. Thus these findings identify an ochre mutation in a human steroid hormone receptor in patients with hereditary 1,25-dihydroxyvitamin D3-resistant rickets.