Molecular mechanisms of hyphophosphatemia and phosphate regulatory protein (Phosphatonin and PEX)
| Project/Area Number |
08671288
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Tokushima University |
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Principal Investigator |
MIYAMOTO Ken-ichi Department of Clinical Nutrition, School of Medicine, Tokushima University, Associate Professor, 医学部, 助教授 (70174208)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1996: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Phosphate / Transporter / Gene Mutation / Mouse / phosphate / transporter / Phosphatonin |
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| Research Abstract |
X-linked hypophosphatemia (XLH) is a genetic disorder of Pi homeostasis characterized by rachitic bone disease, decreased growth rate and short stature, hypophosphatemia, and impaired renal Pi reabsorption. Recently, XLH in humans is caused by mutations in the PEX gene which codes for a protein homologous to neutral endopeptidases. However, the mechanism by which aberrant function of the PEX gene product initiates the pathophysiological cascade underlyning XLH remains unknown. In the present study, we investigated the cellular and molecular mechanisms for the defect of Na/Pi cotransport in murine X-linked Hyp homologs of XLH.Mouse Pex cDNA is predicted to encode a protein of 749 amino acids with 95% identity to the human PEX sequence. The 3'end of Pex cDNA was deleted in the Hyp mouse. Analysis of Na/Pi cotransport in the Hyp mouse showed that there is a 50% decrease both in the type II Na/Pi cotransporter mRNA and in protein. Nuclear run-on assays demonstrated that the decrease in message is caused by decreased transcription of the type II Na/Pi cotransporter gene. Functional analysis of the type II Na/Pi cotransporter gene promoter showed that vitamin D responsive elements and a phosphate responsive element are important for the transcripton in the kidney. In OK cells expressing the luciferase gene under the control of the type II promoter, Hyp mouse serum suppressed the luciferase activity, suggesting that a phosphaturic factor causes directly depressing the transcription of the type II Na/Pi cotransporter gene. Based on these findings, we suggest that PEX is involved in the processing/inactivation of a phosphaturic factor that influences renal Pi handling and that loss of PEX causes abnormal transcriptional control of the type II Na/Pi cotransporter gene.
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Report
(3 results)
Research Products
(18 results)
