Article Text

other Versions

Download PDFPDF
Polymorphisms in E-cadherin (CDH1) result in a mis-localized cytoplasmic protein that is associated with Crohn’s Disease
  1. Aleixo M Muise (aleixo.muise{at}
  1. Hospital for Sick Children, Canada
    1. Thomas D Walters (thomas.walters{at}
    1. Sickkids, Canada
      1. Wioletta K Glowacka
      1. Sickkids, Canada
        1. Anne M Griffiths
        1. Sickkids, Canada
          1. Bo-yee Ngan
          1. Sickkids, Canada
            1. Hui Lan
            1. University of Toronto, Canada
              1. Wei Xu
              1. University of Toronto, Canada
                1. Mark Silverberg
                1. Mt SInai, Canada
                  1. Daniela Rotin (drotin{at}
                  1. Hospital for Sick Children, Canada


                    Background: Patients with Crohn’s Disease (CD) have defects in intestinal epithelial permeability that are inadequately explained by known IBD susceptibility genes. E-cadherin (CDH1) plays a vital role in maintaining the integrity of the intestinal barrier and its cellular localization is disrupted in CD patients.

                    Aim: To determine if polymorphisms in the CDH1 gene are associated with CD and to determine the function associated with these polymorphisms.

                    Methods: The hypothesis was tested using a candidate gene approach using 20 Tag SNPs derived from the HapMap and CD trios. Functional studies were carried out using HapMap cell lines and polarized cell lines (MDCK-1).

                    Results: Here we show that CDH1 is associated with CD in 327 trios (rs10431923 excess transmission of 'TT' genotype; p=0.0020) and is replicated in the Wellcome Trust Case Control Consortium CD data set (TT risk allele; OR 1.2, p=0.005). Patients with the CD risk haplotype (rs12597188, rs10431923, and rs9935563; GTC allelic frequency 21%; p = 0.000016) exhibited increased E-cadherin cytoplasmic accumulation in their intestinal epithelium that may be explained by the presence of a novel truncated form of E-cadherin. Accordingly, expression of this truncated E-cadherin in cultured polarized epithelial cells resulted in abnormal intracellular accumulation of both E-cadherin and β-catenin.

                    Conclusion: The mis-localization of E-cadherin and β-catenin may explain the increased permeability seen in some patients with CD. Thus, the polymorphisms identified in CDH1 are important for understanding the pathogenesis of CD and point to a defect in barrier defense.

                    Statistics from

                    Request Permissions

                    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

                    Supplementary materials