Absence of cell-surface EpCAM in congenital tufting enteropathy

Area of Science:

• Genetics
• Cell Biology
• Gastroenterology

Background:

• Congenital tufting enteropathy (CTE) is a severe neonatal intestinal disorder.
• Mutations in the epithelial cell adhesion molecule (EpCAM) gene are identified as the cause of CTE.
• The mechanism by which diverse EpCAM mutations lead to CTE remains unclear.

Purpose of the Study:

• To investigate the molecular consequences of various EpCAM mutations.
• To understand why different EpCAM mutations result in the same disease phenotype (CTE).

Main Methods:

• Analysis of EpCAM mutations, including a novel intronic variant.
• Assessment of EpCAM protein localization (transmembrane domain, plasma membrane).
• Investigation of EpCAM mutant stability (secretion, degradation).

Main Results:

• Most EpCAM mutations disrupt the transmembrane domain.
• Mutants lacking the transmembrane domain are not routed to the plasma membrane.
• Truncated mutants are either secreted or degraded, leading to loss of cell-surface EpCAM.

Conclusions:

• All identified EpCAM mutations result in a loss of functional cell-surface EpCAM.
• This loss of cell-surface EpCAM is the unifying mechanism leading to congenital tufting enteropathy.
• Understanding EpCAM processing is crucial for CTE pathogenesis.