Abstract
Congenital tufting enteropathy (CTE) is a devastating diarrheal disease seen in infancy that is typically associated with villous changes and the appearance of epithelial tufts. We previously found mutations in epithelial cell adhesion molecule (EpCAM) to be causative in CTE. We developed a knock-down cell model of CTE through transfection of an EpCAM shRNA construct into T84 colonic epithelial cells to elucidate the in vitro role of EpCAM in barrier function and ion transport. Cells with EpCAM deficiency exhibited decreased electrical resistance, increased permeability, and decreased ion transport. Based on mutations in CTE patients, an in vivo mouse model was developed, with tamoxifen-inducible deletion of exon 4 in Epcam resulting in mutant protein with decreased expression. Tamoxifen treatment of Epcam Δ4/Δ4 mice resulted in pathological features of villous atrophy and epithelial tufts, similar to those in human CTE patients, within 4 days post induction. Epcam Δ4/Δ4 mice also showed decreased expression of tight junctional proteins, increased permeability, and decreased ion transport in the intestines. Taken together, these findings reveal mechanisms that may underlie disease in CTE.Key messages Knock-down EpCAM cell model of congenital tufting enteropathy was developed.In vivo inducible mouse model was developed resulting in mutant EpCAM protein.Cells with EpCAM deficiency demonstrated barrier and ion transport dysfunction.Tamoxifen-treated Epcam Δ4/Δ4 mice demonstrated pathological features. Epcam Δ4/Δ4 mice showed improper barrier function and ion transport. Electronic supplementary materialThe online version of this article (doi:10.1007/s00109-014-1239-x) contains supplementary material, which is available to authorized users.
Highlights
Congenital tufting enteropathy (CTE) is a severe intractable diarrheal disease presenting in the neonatal period with chronic watery diarrhea, imbalances in electrolytes, and impaired growth
epithelial cell adhesion molecule (EpCAM) fluorescence was reduced in KD cells (Fig. 1b), but the residual EpCAM in KD cells still appeared to localize to intercellular contacts, as seen in control cells
Tissue from EpcamΔ4/Δ4 mice displayed several characteristics similar to those seen in CTE patients and in our previous constitutive mouse model [15], including villous atrophy and bunching of enterocytes leading to the formation of tufts on villi (Fig. 1d)
Summary
Congenital tufting enteropathy (CTE) is a severe intractable diarrheal disease presenting in the neonatal period with chronic watery diarrhea, imbalances in electrolytes, and impaired growth. The prevalence of CTE is thought to be 1/50,000–1/ 100,000 live births in Western Europe [1]. CTE is an autosomal recessive disease, often seen in families with a history of consanguinity [2]. A diagnosis of CTE is made with recognition of changes in the villi of the small intestinal epithelium. CTE is usually accompanied by villous atrophy, crypt hyperplasia, formation of focal epithelial tufts (bunching of enterocytes) in the small intestinal and colonic mucosae, and absent or mild inflammation [3, 4].
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