A Vitamin D Receptor Gene Polymorphism in the Translation Initiation Codon: Effect on Protein Activity and Relation to Bone Mineral Density in Japanese Women

The effect of a T‐C transition polymorphism at the translation initiation codon of the human vitamin D receptor (VDR) gene on the biological function of the encoded protein was investigated. Of 239 Japanese women volunteers subjected to genotype analysis for this polymorphism, 32 (13%) were genotype...

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Bibliographic Details
Published in:Journal of bone and mineral research 1997-06, Vol.12 (6), p.915-921
Main Authors: Arai, Hidekazu, Miyamoto, Ken‐Ichi, Taketani, Yutaka, Yamamoto, Hironori, Iemori, Yuka, Morita, Kyoko, Tonai, Takeharu, Nishisho, Takehiko, Mori, Shigenobu, Takeda, Eiji
Format: Article
Language:English
Subjects:
Adult
Aged
Alleles
Animals
Base Sequence
Biological and medical sciences
Bone Density - genetics
Codon, Initiator - genetics
COS Cells
DNA - genetics
Exons
Female
Fundamental and applied biological sciences. Psychology
Gene Frequency
Genes. Genome
Genotype
HeLa Cells
Humans
Japan
Middle Aged
Molecular and cellular biology
Molecular genetics
Molecular Sequence Data
Polymorphism, Genetic
Receptors, Calcitriol - genetics
Receptors, Calcitriol - metabolism
Transfection
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Summary:The effect of a T‐C transition polymorphism at the translation initiation codon of the human vitamin D receptor (VDR) gene on the biological function of the encoded protein was investigated. Of 239 Japanese women volunteers subjected to genotype analysis for this polymorphism, 32 (13%) were genotype MM (the M allele is ATG at the putative translation start site), 75 (31%) were genotype mm (the m allele is ACG at the putative translation start site), and 132 (55%) were genotype Mm. The bone mineral density (BMD) in the lumbar spine (L2–L4) was determined for 110 healthy premenopausal women from the volunteers and was shown to be 12.0% greater (p < 0.05) for mm homozygotes than for MM homozygotes. Synthesis of the proteins by the M and m alleles from the cloned cDNAs in vitro and in transfected COS‐7 cells revealed them to have a size of 50 and 49.5 kD, respectively, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. This size difference is consistent with initiation of translation of the M allele‐encoded protein from an ATG codon located at nucleotides +10 to +12 in the conventional open reading frame. The extent of vitamin D–dependent transcriptional activation of a reporter construct 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.
ISSN:0884-0431
1523-4681
DOI:10.1359/jbmr.1997.12.6.915