Open Access
Matriptase drives early-onset intestinal failure in a mouse model of congenital tufting enteropathy
Author(s) -
Roman Szabo,
LuLu K. Callies,
Thomas H. Bugge
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.183392
Subject(s) - biology , enteropathy , mutation , cancer research , atrophy , microbiology and biotechnology , gene , disease , medicine , genetics
Syndromic congenital tufting enteropathy (CTE) is a life-threatening recessive human genetic disorder, which is caused by mutations in SPINT2, encoding the protease inhibitor, HAI-2, and is characterized by severe intestinal dysfunction. We recently reported the generation of a Spint2-deficient mouse model of CTE. Here, we show that the CTE-associated early-onset intestinal failure and lethality of Spint2-deficient mice is caused by unchecked activity of the serine protease, matriptase. Macroscopic and histological defects observed in the absence of HAI-2, including villous atrophy, luminal bleeding, loss of mucin-producing goblet cells, loss of defined crypt architecture and the resulting acute inflammatory response in the large intestine, were all prevented by intestinal-specific inactivation of the St14 gene encoding matriptase. The CTE-associated loss of the cell junctional proteins EpCAM and claudin-7 was also prevented. As a result, inactivation of intestinal matriptase allowed Spint2-deficient mice to gain weight after birth and dramatically increased their life span. These data implicate matriptase as a causative agent in development of CTE and may provide a new target for the treatment of CTE in patients carrying SPINT2 mutations.