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

Content Provider	Springer Nature Link
Author	Salomon, Julie Goulet, Olivier Canioni, Danielle Brousse, Nicole Lemale, Julie Tounian, Patrick Coulomb, Aurore Marinier, Evelyne Hugot, Jean Pierre Ruemmele, Frank Dufier, Jean Louis Roche, Olivier Bodemer, Christine Colomb, Virginie Talbotec, Cécile Lacaille, Florence Campeotto, Florence Cerf Bensussan, Nadine Janecke, Andreas R. Mueller, Thomas Koletzko, Sibylle Bonnefont, Jean Paul Lyonnet, Stanislas Munnich, Arld Poirier, Françoise Smahi, Asma
Copyright Year	2013
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.
Starting Page	299
Ending Page	310
Page Count	12
File Format	PDF
ISSN	03406717
Journal	Human Genetics
Volume Number	133
Issue Number	3
e-ISSN	14321203
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2013-10-19
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Human Genetics Molecular Medicine Gene Function Metabolic Diseases
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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