Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form

Abstract

Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p < 10(-4)) and, for half of them, with choanal atresia (p < 10(-4)). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.

Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasis

“…Both nonsense and missense mutations in SPINT2 have been described in patients with CTE, and it has been demonstrated that missense mutant HAI-2 proteins are less potent inhibitors than control HAI-2 proteins in cellfree in vitro assays of matriptase activity (2,31). To test the prediction that HAI-2 mutant proteins in CTE patients are less effective inhibitors of the HAI-2/matriptase/EpCAM/claudin-7 pathway that we have described herein than control HAI-2 proteins, we carried out several types of experiments.…”

“…Truncating and selected missense mutations in EPCAM (encoding epithelial cell adhesion molecule [EpCAM; CD326]) cause a severe autosomal recessive childhood diarrheal syndrome termed congenital tufting enteropathy (CTE) (1,2). CTE is characterized by widespread small intestinal epithelial dysplasia, and intestinal mucosal biopsies demonstrate distinctive "tufts" of epithelial cells at the tips of blunted villi (1,3).…”

“…Recent studies of CTE patients revealed that a significant minority of individuals harbor mutations in SPINT2 and not in EPCAM (2). SPINT2 encodes a cell membrane-associated Kunitz type 2 serine protease inhibitor, HAI-2, that can regulate the activity of a variety of proteases (15).…”

Kocuria kristinae-caused sepsis in an infant with congenital tufting enteropathy

“…The histopathology shows a crypt hyperplasia, villous atrophy, and epithelial tufts in the small intestine; the enterocytes are formed as a teardrop 5,1,2,6,7,8 . Recent identification of causative mutations of genes such as EpCAM and SPINT2 extend our knowledge about this disease 9,4 .…”

La dysplasie épithéliale intestinale, ou quand l’intestin est sous « deux de tension » cellulaire

“…La DEI est histologiquement définie par un épithélium dysplasique caractéristique, prenant de façon hétérogène un aspect pseudostratifié où les entérocytes s'accumulent sous forme de houppettes ou « tufts » [6], qui touchent jusqu'à 70 % des villosités à un stade avancé [6]. La preuve directe de la participation d'EpCAM (epithelial cell adhesion molecule) dans le maintien de la monocouche épithéliale intestinale a été fournie par une récente étude clinique où des mutations faux-sens ou non-sens du gène EPCAM, conduisant respectivement à la perte d'expression ou à des formes tronquées de la protéine, ont été corrélées au développe-ment de la DEI chez 73 % des patients [7]. EpCAM est une protéine spécifi-quement exprimée dans les épithéliums monostratifiés [8].…”