Congenital tufting enteropathy (CTE) is an intractable diarrheal disease of infancy presenting with profuse watery diarrhea, electrolyte imbalances, and impaired growth. Intestinal pathology includes villous atrophy, crypt hyperplasia and epithelial tufts leading to intestinal failure due to defects in the intestinal epithelial barrier s reported in our recent publication. The significant morbidity and mortality result in an unmet need for effective treatments that requires a better understanding of disease pathophysiology. Our discovery of mutations in epithelial cell adhesion molecule (EpCAM) as the cause of disease in CTE patients, provided a crucial step allowing for accurate and early diagnosis of this severe gastrointestinal disorder. While deficiency of EpCAM in a colonic cell line can account for ion transport and barrier defects, we have yet to understand how mutations in EpCAM are responsible for the structural abnormalities of the villi in CTE. Recently, we have made an exciting observation that many mutant forms of EpCAM are sequestered in the endoplasmic reticulum (ER) compared with the normal localization of WT EpCAM at the plasma membrane. Because the ER is the first step of the secretory pathway, dysregulation of ER function potentially caused by the accumulation of mutant EpCAM might represent the key molecular event responsible for disease phenotype. We have identified several different EpCAM mutations in CTE patients. Some mutations in CTE patients result in a complete absence of EpCAM expression, and these patients have been shown to have a milder disease phenotype. Most mutations result in the expression of mutant EpCAM protein, which accumulates in the ER, as revealed by significant ER distention by ultrastructural analysis. Accumulation of unfolded proteins is known to activate the Unfolded Protein Response (UPR) signaling pathway. In fact, we have confirmed that some hallmarks of the UPR occur in our disease models. Thus, we now propose to test our central hypothesis that the UPR is activated in CTE patients' intestines and that ER stress, caused by mutant EpCAM, is responsible for the structural and functional abnormalities of the villi in CTE patients. Towards these goals, we will focus on two questions: 1) What aspects of UPR are triggered by mutant EpCAM, and what are the functional consequences of UPR activation leading to disease phenotype and 2) What alterations in cell fate cause the development of aberrant villi in CTE intestine? The use of tools to study UPR activation status, our murine models and our recent development of 3D in vitro cell culture model that mimic the structural complexity of the intestine, will greatly facilitate our study.

Public Health Relevance

Congenital Tufting Enteropahy is severe, life threatening intractable diarrheal diseases of infancy that presents in the neonatal period. The goal of this project is to identify the underlying pathophysiology by which mutations of EpCAM lead to the intestinal epithelial disorganization characteristic of this disease. This study will advance our understanding of EpCAM's role in the intestine, CTE, and diarrheal diseases and eventually aid in developing new treatments.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Greenwel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California, San Diego
Schools of Medicine
La Jolla
United States
Zip Code
Pathak, Sagar J; Mueller, James L; Okamoto, Kevin et al. (2018) EPCAM mutation update: Variants associated with congenital tufting enteropathy and Lynch syndrome. Hum Mutat :