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Congenital tufting enteropathy (CTE) is a life-threatening hereditary disease that is characterized by enteric mucosa tufting degeneration and early onset, severe diarrhea. Loss-of-function mutations of the human  EPCAM  gene ( TROP1 ,  TACSTD1 ) have been indicated as the cause of CTE. However, loss of  mTrop1/Epcam  in mice appeared to lead to death  in utero , due to placental malformation. This and indications of residual Trop-1/EpCAM expression in cases of CTE cast doubt on the role of  mTrop1/Epcam  in this disease. The aim of this study was to determine the role of  TROP1 / EPCAM  in CTE and to generate an animal model of this disease for molecular investigation and therapy development. Using a rigorous gene-trapping approach, we obtained  mTrop1/Epcam  -null (knockout) mice. These were born alive, but failed to thrive, and died soon after birth because of hemorrhagic diarrhea. The intestine from the  mTrop1/Epcam  knockout mice showed intestinal tufts, villous atrophy and colon crypt hyperplasia, as in human CTE. No structural defects were detected in other organs. These results are consistent with  TROP1 / EPCAM  loss being the cause of CTE, thus providing a viable animal model for this disease, and a benchmark for its pathogenetic course. In the affected enteric mucosa, E-cadherin and β-catenin were shown to be dysregulated, leading to disorganized transition from crypts to villi, with progressive loss of membrane localization and increasing intracellular accumulation, thus unraveling an essential role for Trop-1/EpCAM in the maintenance of intestinal architecture and functionality.  Supporting information is available for this article.

mTrop1/Epcam Knockout Mice Develop Congenital Tufting Enteropathy through Dysregulation of Intestinal E-cadherin/β-catenin