Identification of EpCAM as the Gene for Congenital Tufting Enteropathy

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Date of download: 6/22/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Identification of a Novel TP53 Cancer Susceptibility.

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Identification of EpCAM as the Gene for Congenital Tufting Enteropathy Mamata Sivagnanam, James L. Mueller, Hane Lee, Zugen Chen, Stanley F. Nelson, Dan Turner, Stanley H. Zlotkin, Paul B. Pencharz, Bo–Yee Ngan, Ondrej Libiger, Nicholas J. Schork, Joel E. Lavine, Sharon Taylor, Robert O. Newbury, Richard D. Kolodner, Hal M. Hoffman Gastroenterology Volume 135, Issue 2, Pages 429-437 (August 2008) DOI: 10.1053/j.gastro.2008.05.036 Copyright © 2008 AGA Institute Terms and Conditions

Figure 1 Schematic of duodenal mucosa showing histology of (A) normal intestinal villus and (B) congenital tufting enteropathy villus with crowded epithelial cells forming tufts, villus atrophy. (C) H&E-stained duodenal tissue (original magnification, 20×) from affected patients (P1 and P2) exhibiting tufting and crowding of epithelial cells. Gastroenterology 2008 135, 429-437DOI: (10.1053/j.gastro.2008.05.036) Copyright © 2008 AGA Institute Terms and Conditions

Figure 2 (A) Pedigree 1: family with congenital tufting enteropathy including affected patients (P1 and P2) and unaffected siblings (U1 and U2). Generations are indicated by Roman numerals on the left. Affected patients (P1 and P2) are double second cousins. (B) Homozygosity mapping: genome-wide homozygosity intervals are plotted for individuals P1 and P2. The y-axis indicates the length of the intervals, and the x-axis shows relative chromosomal position with chromosomes indicated across the top of each panel. The homozygous blocks shared between P1 and P2 are shown in the bottom bar graph (P1 and P2). The interval identified as homozygous in both individuals is highlighted with a gray box bar across all 3 panels. (C) Haplotype structure of the pedigree. Homozygous blocks on chromosome 2p21 that are shared by the 2 affected descendants (P1 and P2) are shown as black bars with genotypes at the flanking ends shown with SNP identification numbers from dbSNP. Two hundred twenty SNPs in the middle of each block are not shown for simplicity because all 220 SNPs are homozygous and common in both affected individuals. (D) EpCAM exon 4 donor splice site mutation in pedigree 1: nucleotides across x-axis with mutation in bold. Coding nucleotides are shown in uppercase letters and intronic nucleotides in lowercase letters. Homozygous mutant affected patients (P1 and P2), heterozygous unaffected sibling (U2), normal control (C1). Gastroenterology 2008 135, 429-437DOI: (10.1053/j.gastro.2008.05.036) Copyright © 2008 AGA Institute Terms and Conditions

Figure 3 (A) Genomic region surrounding EpCAM with exons labeled and CTE patient (P1, P2, P3, P4) mutations noted. Nucleotide and amino acid coordinates of mutations are shown assuming the A of the ATG codon is nucleotide 1. (B) Schematic representation of wild-type and mutant RNA with variant splicing of exon 4 as seen in patients P1 and P2. (C) EpCAM protein with epidermal growth factor domains (EGF I and II) and transmembrane region (TM). Dashed box represents area coded by exon 4. Predicted location of cysteine to tyrosine missense mutation at aa position 66 (C66Y) found in patient P4. (D) RT-PCR products of EpCAM from cDNA of control (WT) and affected patient (MUT) duodenal tissue demonstrating smaller product size of mutant. (E) Fluorescent immunohistochemistry of duodenal biopsy specimens with 323/A3 EpCAM antibody (green) wild-type (WT), mutant (MUT), and isotype control (IC) demonstrating minimal nonspecific staining of affected patient tissue (MUT) and epithelial predominance unaffected patient tissue (WT). (F) Patient tissue Western blot analysis demonstrating decreased protein expression of EpCAM (mAb sc-25308 and 311-1k1) in CTE-affected patient (P2) as compared with normal (N1 and N4) and inflammatory bowel disease patient (N6), equal levels of E-cadherin (mAb EP700y), and actin. Two hundred ninety-three cell Western blot analyses of 293 cells transfected with wild-type EpCAM (WT), mutant EpCAM (lacking exon 4) (MUT), and nontransfected cells (NT) are shown. Detectable bands corresponding to EpCAM using mAb sc-25308, but not 311-1k1, consistent with its epitope near the deleted exon 4 are shown. Gastroenterology 2008 135, 429-437DOI: (10.1053/j.gastro.2008.05.036) Copyright © 2008 AGA Institute Terms and Conditions