Matriptase drives early-onset intestinal failure in a mouse model of congenital tufting enteropathy

Development. 2019 Nov 18;146(22):dev183392. doi: 10.1242/dev.183392.

Abstract

Syndromic congenital tufting enteropathy (CTE) is a life-threatening recessive human genetic disorder that 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 lifespan. These data implicate matriptase as a causative agent in the development of CTE and may provide a new target for the treatment of CTE in individuals carrying SPINT2 mutations.This article has an associated 'The people behind the papers' interview.

Keywords: Enteropathy; EpCAM; Epithelial barrier; HAI-2; Intestinal development; Membrane-anchored serine protease.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Claudins / metabolism
  • Crosses, Genetic
  • Diarrhea, Infantile / genetics*
  • Diarrhea, Infantile / pathology*
  • Disease Models, Animal
  • Epithelial Cell Adhesion Molecule / metabolism
  • Epithelium / metabolism
  • Female
  • Genotype
  • Hemorrhage
  • Intestines / pathology*
  • Malabsorption Syndromes / genetics*
  • Malabsorption Syndromes / pathology*
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phenotype
  • Serine Endopeptidases / genetics*
  • Serine Endopeptidases / metabolism*

Substances

  • Claudins
  • Cldn7 protein, mouse
  • Epithelial Cell Adhesion Molecule
  • Membrane Proteins
  • Spint2 protein, mouse
  • Serine Endopeptidases
  • matriptase
  • St14 protein, mouse

Supplementary concepts

  • Diarrhea 5, With Tufting Enteropathy, Congenital