Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells
Expressional and functional studies of Wolframin, the gene function deficient in Wolfram syndrome, in mice and patient cells
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DOI：
10.1016/j.exger.2005.06.008
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发表时间：
2005-08-01
影响因子：
3.9
通讯作者：
Weiher, H
中科院分区：
文献类型：
--
作者：
Philbrook, C;Fritz, E;Weiher, H
Wolfram综合征是一种常染色体隐性遗传的神经内分泌系统退行性疾病。糖尿病是其主要症状。患者显示编码890个氨基酸的疏水性跨膜蛋白的钨蛋白（WFS 1）基因突变。这种蛋白质初步定位于小鼠和大鼠细胞的内质网（ER）中。缺乏WFS 1基因的小鼠在ER应激诱导后显示胰腺P细胞变性，我们在这里使用了针对钨蛋白亚结构的抗体，以分析其表达和定位。在小鼠的胰腺β细胞和边缘系统中均检测到表达。使用大鼠胰岛素瘤细胞系KIN 5AH和分级的灌洗脑组织，我们证实了钨蛋白定位于内质网。对患者的原代成纤维细胞的表达谱显示了糖尿病相关的质膜糖蛋白（PC-1）基因的下调，和fibulin-3，一个与衰老有关的基因的上调。然而，细胞增殖与非突变细胞无法区分。与小鼠胰岛上获得的数据相反，我们发现ER应激诱导后细胞凋亡没有增加，而是在没有WFS 1功能的情况下通过星形孢菌素治疗。这表明WFS 1缺陷在程序性细胞死亡中的新作用。(c)2005年爱思唯尔公司All rights reserved.
Wolfram Syndrome is an autosomal recessive degenerative disorder of the neuroendocrine system. Diabetes mellitus is its lead symptom. Patients show mutations in the wolframin (WFS1) gene coding for a hydrophobic transmembrane protein of 890 amino acids. This protein was preliminarily localised in the endoplasmatic reticulum (ER) in cells of mice and rats. Mice lacking the WFS1 gene display degeneration of pancreatic P-cells following induction of ER stress.We here used antibodies against substructures of the wolframin protein in order to analyse its expression and localisation. Expression was detected in both pancreatic beta-cells and the limbic system of mice. Using the rat insulinoma cell line KIN 5AH and fractionated douse brain tissue, we confirmed wolframin localisation to the endoplasmic reticulum.Expression profiling on patient's primary fibroblasts revealed down-regulation of the diabetes associated plasma membrane glycoprotein (PC-1) gene, and up-regulation of fibulin-3, a gene connected to senescence. However, cell proliferation was indistinguishable from non-mutated cells. In contrast to data obtained on murine pancreatic islets, we found no increased apoptosis following induction of ER stress but rather by staurosporine treatment in the absence of WFS1 function. This indicates a new role of WFS1 deficiency in programmed cell death. (c) 2005 Elsevier Inc. All rights reserved.