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Molecular mechanisms of hyphophosphatemia and phosphate regulatory protein (Phosphatonin and PEX)

低磷血症和磷酸盐调节蛋白（磷酸钙和PEX）的分子机制

基本信息

批准号：
08671288
负责人：
MIYAMOTO Ken-ichi
金额：
$ 1.41万
依托单位：
Tokushima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671288/
关键词：
Phosphate Transporter Gene Mutation Mouse phosphate transporter Phosphatonin

项目摘要

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.

X-连锁低磷血症（XLH）是一种遗传性的Pi稳态紊乱，其特征为佝偻病性骨病、生长速度减慢和身材矮小、低磷血症和肾Pi重吸收受损。最近，人类的XLH是由编码与中性内肽酶同源的蛋白质的PEX基因突变引起的。然而，PEX基因产物的异常功能启动XLH基础的病理生理级联反应的机制仍然未知。在本研究中，我们研究了小鼠XLH的X连锁Hyp同源物中Na/Pi共转运缺陷的细胞和分子机制。小鼠Pex cDNA预测编码749个氨基酸的蛋白质，与人PEX序列具有95%的同源性。在Hyp小鼠中缺失Pex cDNA的3 '端。Na/Pi共转运的Hyp小鼠的分析表明，有一个50%的减少，在II型Na/Pi共转运蛋白的mRNA和蛋白质。核运行试验表明，消息的减少是由II型Na/Pi协同转运蛋白基因的转录减少引起的。II型Na/Pi协同转运蛋白基因启动子的功能分析表明，维生素D响应元件和磷酸盐响应元件对肾脏中的转录子是重要的。在OK细胞表达的荧光素酶基因的控制下的II型启动子，Hyp小鼠血清抑制荧光素酶活性，表明磷酸化因子的原因直接抑制II型Na/Pi共转运蛋白基因的转录。基于这些研究结果，我们认为，PEX参与的磷酸尿因子的处理/失活，影响肾Pi的处理和PEX的损失导致II型Na/Pi协同转运蛋白基因的异常转录控制。