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Molecular effects of the tissue-nonspecific alkaline phosphatase gene polymorphism (787T > C) associated with bone mineral density.

Abstract
Based on studies of hypophosphatasia, which is a systemic skeletal disorder resulting from tissuenonspecific alkaline phosphatase (TNSALP) deficiency, TNSALP was suggested to be indispensable for bone mineralization. Recently, we demonstrated that there was a significant difference in bone mineral density (BMD) among haplotypes, which was lowest among TNSALP (787T [Tyr-246Tyr]) homozygotes, highest among TNSALP (787T > C [Tyr246His]) homozygotes, and intermediate among heterozygotes. To analyze protein translated from the TNSALP gene 787T > C, we performed the biosynthesis of TNSALPs using TNSALP cDNA expression vectors. TNSALP (787T) and TNSALP (787T > C) were synthesized similarly as a high-mannose-type 66-kDa form, becoming an 80-kDa form. Expression of the human 787T > C TNSALP gene using the cultured mouse marrow stromal cell line ST2 demonstrated that the protein translated from 787T > C exhibited an ALP-specific activity similarly to that of 787T. Interestingly, the Km value for TNSALP in ST2 cells transfected with the 787T > C TNSALP gene was decreased significantly compared to that of cells carrying the 787T gene (P < 0.01). These results suggest that the significant difference in Km values between the proteins translated from 787T > C and 787T may contribute to regulatory effects on bone metabolism.
AuthorsNatsuko Sogabe, Kimimitsu Oda, Hiroyuki Nakamura, Hideo Orimo, Hisashi Watanabe, Takayuki Hosoi, Masae Goseki-Sone
JournalBiomedical research (Tokyo, Japan) (Biomed Res) Vol. 29 Issue 4 Pg. 213-9 (Aug 2008) ISSN: 1880-313X [Electronic] Japan
PMID18724009 (Publication Type: Journal Article)
Chemical References
  • Isoenzymes
  • Alkaline Phosphatase
Topics
  • Alkaline Phosphatase (genetics, metabolism)
  • Animals
  • Bone Density (genetics)
  • Cell Line
  • Haplotypes
  • Humans
  • Hypophosphatasia (genetics, metabolism)
  • Isoenzymes (genetics, metabolism)
  • Mice
  • Models, Molecular
  • Polymorphism, Genetic
  • Protein Conformation
  • Stromal Cells (cytology, physiology)

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