Muise Aleixo M, Walters Thomas, Wine Eytan, Griffiths Anne M, Turner Dan, Duerr Richard H, Regueiro Miguel D, Ngan Bo-Yee, Xu Wei, Sherman Philip M, Silverberg Mark S, Rotin Daniela
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, 555 University Ave, Toronto, Ontario, Canada.
Curr Biol. 2007 Jul 17;17(14):1212-8. doi: 10.1016/j.cub.2007.06.013. Epub 2007 Jul 5.
Inflammatory bowel disease (IBD), a relatively common chronic debilitating intestinal illness, is composed of two broadly defined groups, Crohn's disease (CD) and ulcerative colitis (UC). Although several susceptibility genes for CD have been recently described, susceptibility genes exclusive for UC have not been forthcoming. Here, we show that receptor protein-tyrosine phosphatase sigma (PTPRS-encoding PTPsigma) knockout mice spontaneously develop mild colitis that becomes severe when challenged with two known inducers of colitis. We also demonstrate that E-cadherin and beta-catenin, two important adherens junction proteins involved in maintenance of barrier defense in the colon, act as colonic substrates for PTPsigma. Furthermore, we show that three SNPs (rs886936, rs17130, and rs8100586) that flank exon 8 in the human PTPRS gene are associated with UC. The presence of these SNPs is associated with novel splicing that removes the third immunoglobulin-like domain (exon 9) from the extracellular portion of PTPsigma, possibly altering dimerization or ligand recognition. We propose that polymorphisms in the human PTPRS gene lead to ulcerative colitis.
炎症性肠病（IBD）是一种相对常见的慢性致残性肠道疾病，由两个大致定义的组组成，即克罗恩病（CD）和溃疡性结肠炎（UC）。尽管最近已经描述了几种CD的易感基因，但尚未发现UC特有的易感基因。在这里，我们表明受体蛋白酪氨酸磷酸酶σ（编码PTPσ的PTPRS）基因敲除小鼠会自发发展为轻度结肠炎，当受到两种已知的结肠炎诱导剂攻击时会变得严重。我们还证明，E-钙黏蛋白和β-连环蛋白这两种参与维持结肠屏障防御的重要黏附连接蛋白，是PTPσ的结肠底物。此外，我们表明人类PTPRS基因外显子8侧翼的三个单核苷酸多态性（rs886936、rs17130和rs8100586）与UC相关。这些单核苷酸多态性的存在与新的剪接有关，该剪接从PTPσ的细胞外部分去除了第三个免疫球蛋白样结构域（外显子9），可能改变二聚化或配体识别。我们提出人类PTPRS基因的多态性导致溃疡性结肠炎。
