ヒトビタミンD受容体遺伝子の構造と機能解析

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The human vitamin D receptor(VDR)gene is comprised of 11 exons that together with intervening introns span approximately 75 kilobases. The noncoding 5' end of the gene includes exons 1A, 1B, and 1C. Eight additional exons (exons 2-9) encode the structural portion of the VDR gene product. While primer extension and S1 nuclease mapping studies reveal several common transcriptional start sites, three unique mRNA species are produced as a result of the differential splicing of exons 1B and 1C. Fusion of DNA fragments containing putative promoter sequences upstream of the luciferase structural gene resulted in significant reporter activity. An intron fragment 3' of exon 1C conferred retinoic acid responsivity when fused to a reporter gene plasmid, suggesting a molecular mechanism for the previously observed ability of retinoic acid to induce the VDR. The effect of a T-C transition polymorphism at the translation initiation codon of the human VDR gene on the biological function of the encoded protein was investigated. Of 239 Japanese women volunteers subjected to genotype analysis for this polymorphism, 13% were genotype MM (the M allele is ATG at the putative translation start site), 31% were genotype mm (the m allele is ACG at the putative translation start site), and 55% were genotype Mm. The bone mineral density (BMD) in the lumbar spine (L2-L4) was determined for 110 healthy premenopausal women and was shown to be 12.0% greater for mm homozygotes than for MM homozygotes. The extent of vitamin D-dependent transcriptional activation of a reporter constract under the control of a vitamin D response element in transfected HeLa cells was 〜 1.7-fold greater for the m type VDR than for the M type protein. These results suggest that the polymorphism at the translation start site of the VDR gene may modulate BMD in premenopausal Japanese women.
日本ビタミン学会の論文
1998-12-25

ヒトビタミンD受容体遺伝子の構造と機能解析

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