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Identification of EpCAM as the gene for congenital tufting enteropathy.

Abstract：

BACKGROUND & AIMS:Congenital tufting enteropathy (CTE) is a rare autosomal recessive diarrheal disorder presenting in the neonatal period. CTE is characterized by intestinal epithelial cell dysplasia leading to severe malabsorption and significant morbidity and mortality. The pathogenesis and genetics of this disorder are not well understood. The objective of this study was to identify the gene responsible for CTE. METHODS:A family with 2 children affected with CTE was identified. The affected children are double second cousins providing significant statistical power for linkage. Using Affymetrix 50K single nucleotide polymorphism (SNP) chips, genotyping was performed on only 2 patients and 1 unaffected sibling. Direct DNA sequencing of candidate genes, reverse-transcription polymerase chain reaction, immunohistochemistry, and Western blotting were performed on specimens from patients and controls. RESULTS:SNP homozygosity mapping identified a unique 6.5-Mbp haplotype of homozygous SNPs on chromosome 2p21 where approximately 40 genes are located. Direct sequencing of genes in this region revealed homozygous G>A substitution at the donor splice site of exon 4 in epithelial cell adhesion molecule (EpCAM) of affected patients. Reverse-transcription polymerase chain reaction of duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4 in affected patients. Immunohistochemistry and Western blot of patient intestinal tissue revealed decreased expression of EpCAM. Direct sequencing of EpCAM from 2 additional unrelated patients revealed novel mutations in the gene. CONCLUSIONS:Mutations in the gene for EpCAM are responsible for CTE. This information will be used to gain further insight into the molecular mechanisms of this disease.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Sivagnanam M,Mueller JL,Lee H,Chen Z,Nelson SF,Turner D,Zlotkin SH,Pencharz PB,Ngan BY,Libiger O,Schork NJ,Lavine JE,Taylor S,Newbury RO,Kolodner RD,Hoffman HM

doi

10.1053/j.gastro.2008.05.036

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

429-37

issue

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(08)00856-1

journal_volume

135

pub_type

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Identification of EpCAM as the gene for congenital tufting enteropathy.