title: Functional consequences of EpCam mutation in mice and men.
abstract: Congenital tufting enteropathy (CTE) is a severe diarrheal disease of infancy characterized by villous changes and epithelial tufts. We previously identified mutations in epithelial cell adhesion molecule (EpCAM) as the cause of CTE. We developed an in vivo mouse model of CTE based on EpCAM mutations found in patients with the aim to further elucidate the in vivo role of EpCAM and allow for a direct comparison to human CTE. Using Cre-LoxP recombination technology, we generated a construct lacking exon 4 in Epcam. Epcam(Δ4/Δ4) mice and CTE patient intestinal tissue integrity was analyzed by histology using both light immunohistochemistry and electron microscopy. Epcam(Δ4/Δ4) mice demonstrate neonatal lethality and growth retardation with pathological features, including epithelial tufts, enterocyte crowding, altered desmosomes, and intercellular gaps, similar to human CTE patients. Mutant EpCAM protein is present at low levels and is mislocalized in the intestine of Epcam(Δ4/Δ4) mice and CTE patients. Deletion of exon 4 was found to decrease expression of both EpCAM and claudin-7 causing a loss of colocalization, functionally disrupting the EpCAM/claudin-7 complex, a finding for the first time confirmed in CTE patients. Furthermore, compared with unaffected mice, mutation of Epcam leads to enhanced permeability and intestinal cell migration, uncovering underlying disease mechanisms.
authors: Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, University of California San Diego, La Jolla, California;
authors: James L
authors: JL
authors: Mueller
authors: Matthew D
authors: MD
authors: McGeough
authors: Carla A
authors: CA
authors: Peña
authors: Mamata
authors: M
authors: Sivagnanam
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D057167:Claudins / Q000378:metabolism; D003968:Diarrhea, Infantile / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000071858:Epithelial Cell Adhesion Molecule; D005091:Exons; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008286:Malabsorption Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010539:Permeability; D010641:Phenotype; D014162:Transfection
chemical_list: D000951:Antigens, Neoplasm; C473255:CLDN7 protein, human; D015815:Cell Adhesion Molecules; D057167:Claudins; C507360:Cldn7 protein, mouse; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule
keywords: EpCam; chronic diarrhea; congenital tufting enteropathy; intestinal failure; mouse model