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The point mutation of polymeric immunoglobulin receptor and IgA nephropathy

多聚免疫球蛋白受体点突变与IgA肾病

基本信息

批准号：
18592071
负责人：
ASANO Masatake
金额：
$ 1.5万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18592071/
关键词：
pIgR IgA nephrop athy point mutation free secretory component 多量体免疫グロブリンレセプター

项目摘要

Comparison of the genomic DNA sequences of the peripheral blood samples taken from healthy individuals and IgA-nephropathy (IgAN) patients has revealed that, in IgAN-patients, high-score DNA mutation was detected in polymeric immunoglobulin receptor (pIgR) DNA. The mutation was frequently detected at the position of 580 aa and resulted in the substitution of alanine to valine residue. The aim of this study was to compare the biochemical properties of wild type and mutant pIgR (A580V) molecules and to elucidate the correlation of this mutation to IgAN. Both cDNA was introduced into mammalian expression vector and used for transfection. Both transfectants were labeled by metabolic labeling or surface biotinylation methods. After labeling, the amount of free secretory component (fSC ; the extracellular part of pIgR) released in the culture medium was estimated. However, no differences were observed between wt and mutant. The glutamic acid in the positions 606 and 607 were known to be conserved between several animal species and thought to be a cleaving site of the exrtracellular portion of pIgR. By substituting these two residues to alanine residue with site-directed mutagenesis, we examined the influence of these changes on the release of fSC. As results, no changes were observed. These results suggested that enzymatic cleavage of pIgR might be differentially. controlled between epithelial and fibroblastic cells.

对健康个体和 IgA 肾病 (IgAN) 患者外周血样本的基因组 DNA 序列进行比较发现，在 IgAN 患者中，在聚合免疫球蛋白受体 (pIgR) DNA 中检测到高分 DNA 突变。该突变经常在 580 个氨基酸位置检测到，导致丙氨酸残基替换为缬氨酸残基。本研究的目的是比较野生型和突变型 pIgR (A580V) 分子的生化特性，并阐明该突变与 IgAN 的相关性。将两种cDNA导入哺乳动物表达载体并用于转染。两种转染子均通过代谢标记或表面生物素化方法进行标记。标记后，估计培养基中释放的游离分泌成分（fSC；pIgR 的细胞外部分）的量。然而，在野生型和突变体之间没有观察到差异。已知606和607位的谷氨酸在几种动物物种之间是保守的，并且被认为是pIgR细胞外部分的切割位点。通过定点诱变将这两个残基替换为丙氨酸残基，我们检查了这些变化对 fSC 释放的影响。结果，没有观察到任何变化。这些结果表明 pIgR 的酶促裂解可能存在差异。控制在上皮细胞和成纤维细胞之间。