Alternative titles; symbols
HGNC Approved Gene Symbol: EPCAM
Cytogenetic location: 2p21 Genomic coordinates (GRCh38) : 2:47,369,311-47,387,020 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p21 | Diarrhea 5, with tufting enteropathy, congenital | 613217 | Autosomal recessive | 3 |
| Lynch syndrome 8 | 613244 | Autosomal dominant | 3 |
Spurr et al. (1986) characterized a human cell surface antigen that is defined by the monoclonal antibody AUAI. The gene product was expressed only on epithelial cells. The AUAI antibody detected a single 35-kD protein.
Szala et al. (1990) cloned the cDNA for GA733-2 from an expression colorectal carcinoma cell cDNA library transfected into COS cells and immunoselected with the GA733 monoclonal antibody. The predicted 314-residue protein is processed to the mature antigen of 232 amino acids. The glycosylated protein is predominantly 40 kD, although other species are observed. The same cDNA was identified independently by Strnad et al. (1989) from the lung adenocarcinoma cell line UCLA-P3 and designated KSA. Likewise, Perez and Walker (1989) obtained the identical cDNA, which they designated KS1/4 antigen. GA733-2 is about 49% similar to GA733-1 (137290). Both GA733 antigens have similar hydropathy plots, which include 2 hydrophobic regions. A domain at the amino end is predictive of signal peptides, while the hydrophobic domain at the carboxyl end is most likely a membrane spanning sequence. Northern blot analysis demonstrated a 1.45- to 1.5-kb transcript in cell lines derived from colorectal and pancreatic carcinomas. The mRNA was also detected in normal colon and in lung and colon adenocarcinoma lines.
Schnell et al. (2013) showed that the deduced 314-amino acid EPCAM protein has an N-terminal signal sequence, followed by a EPCAM motif-1, a thyroglobulin (188450) type 1A-like repeat, a transmembrane domain near the C terminus, and a short cytoplasmic tail. The large extracellular domain also has 3 possible sites for N-glycosylation. Schnell et al. (2013) stated that EPCAM is expressed on the basolateral membrane of intestinal epithelium with a gradient of high expression in crypts to low expression at villi. SDS-PAGE of transfected HEK293T cells detected EPCAM at an apparent molecular mass of about 39 kD. A proportion of EPCAM was secreted into the culture medium.
Linnenbach et al. (1993) showed that the gene encoding GA733-2 (M4S1) contains 9 exons. From studies of the GA733-2 genomic sequence and comparison of the promoter regions of both GA733-2 and GA733-1 genes, the authors concluded that GA733-1 was formed by the retrotransposition of the 9-exon GA733-2 gene via an mRNA intermediate.
Spurr et al. (1986) mapped the MIC18 gene to human chromosome 2 by analysis of human-mouse somatic cell hybrids. By PCR analysis, Durbin et al. (1990) confirmed the mapping of MIC18 to chromosome 2. Calabrese et al. (2001) mapped the EPCAM (TACSTD1) gene to 2p21 by fluorescence in situ hybridization.
Congenital Tufting Enteropathy
In a kindred of Mexican American descent in which 2 boys who were double second cousins had congenital tufting enteropathy (CTE) (DIAR5; 613217) mapping to chromosome 2, Sivagnanam et al. (2008) identified homozygosity for a splice site mutation in the EPCAM gene in both affected individuals (185535.0001). The parents and an unaffected sib were heterozygous for the mutation, which was not detected in 400 controls, including 200 of Mexican American descent. Analysis of EPCAM in 3 additional unrelated patients with CTE revealed homozygosity for another splice site mutation in a native Canadian patient (185535.0002) and heterozygosity for a missense mutation in a Russian patient (C66Y; 185535.0003); no mutation was identified in the remaining patient. Immunohistochemical staining of duodenal biopsy tissue showed absent or markedly decreased epithelial EPCAM staining in all 5 patients compared to age-matched controls and 1 control patient with inflammatory bowel disease (see IBD1, 266600). Schnell et al. (2013) restudied the Russian patient in whom Sivagnanam et al. (2008) detected only a heterozygous C66Y substitution in the EPCAM gene, and identified an additional intronic mutation (185535.0009), which was predicted to result in premature termination within the EPCAM ectodomain.
In a patient with CTE who developed chronic inflammatory arthritis at 4 years of age, Al-Mayouf et al. (2009) identified homozygosity for a 1-bp insertion in the EPCAM gene (185535.0004).
In a female infant with congenital tufting enteropathy, Sivagnanam et al. (2010) identified homozygosity for a nonsense mutation in the EPCAM gene (R138X; 185535.0007).
Schnell et al. (2013) expressed wildtype EPCAM and 7 mutant constructs mimicking mutations that cause congenital tufting enteropathy in HEK293T cells. SDS-PAGE and immunohistochemical analysis revealed that most mutant proteins were expressed at lower levels than wildtype EPCAM and that none of the mutant proteins localized to the plasma membrane. Most truncation mutations resulted in loss of the C-terminal transmembrane domain, and several mutant proteins were either secreted or degraded in the ER. Mutations that resulted in a frameshift were also degraded in the ER.
In a study of 57 patients from 46 families who were clinically diagnosed with congenital tufting enteropathy, Salomon et al. (2014) identified EPCAM mutations in 41 patients (73%) and SPINT2 (605124) mutations in 12 patients (21%) (see DIAR3, 270420). All patients with SPINT2 mutations exhibited syndromic features, including superficial punctate keratitis and choanal atresia, as well as other atresias, dermatologic anomalies, and bone malformations, whereas the patients with EPCAM mutations had isolated congenital diarrhea.
Lynch Syndrome 8
Ligtenberg et al. (2009) described patients from Dutch and Chinese families with MSH2 (609309)-deficient colorectal tumors (LYNCH8; 613244) carrying heterozygous germline deletions of the last exons of TACSTD1 (185535.0005, 185535.0006), the gene directly upstream of MSH2. The deletions caused the transcription of TACSTD1 to extend into MSH2. The MSH2 promoter in cis with the deletion was methylated in EPCAM-positive but not in EPCAM-negative normal tissues, thus revealing a correlation between activity of the mutated TACSTD1 allele and epigenetic inactivation of the corresponding MSH2 allele. Gene silencing by transcriptional read-through of a neighboring gene in either sense or antisense direction could represent a general mutational mechanism. Depending on the expression pattern of the neighboring gene that lacks its normal polyadenylation signal, this may cause either generalized or mosaic patterns of epigenetic inactivation.
Kuiper et al. (2011) analyzed 45 Lynch syndrome families with EPCAM deletions, including 27 families ascertained through targeted genomic screens in cohorts of unexplained Lynch-like families and 18 previously studied families with known EPCAM deletions. Overall, 19 different deletions were found, all of which included the last 2 exons and the transcription termination signal of EPCAM. All deletions appeared to originate from Alu-repeat mediated recombination events; in 17 cases, regions of microhomology around the breakpoints were found, suggesting nonallelic homologous recombination as the most likely mechanism. Within the Netherlands and Germany, EPCAM deletions appeared to represent at least 2.8% and 1.1% of the confirmed Lynch syndrome families, respectively. Kuiper et al. (2011) concluded that 3-prime EPCAM deletions are a recurrent cause of Lynch syndrome and should be sought in routine Lynch syndrome diagnostic testing.
Linnenbach et al. (1993) localized the GA733-2 (EPCAM) gene to 4q by analysis of human/rodent somatic cell hybrids.
Meyaard et al. (2001) presented evidence suggesting that EPCAM is a ligand for LAIR1 (602992) and LAIR2 (602993). However, the authors later retracted their paper after further studies showed that EPCAM is not a ligand for LAIR1 and LAIR2 and that their prior results were an artifact resulting from contamination.
In a kindred of Mexican American descent in which 2 boys who were double second cousins had congenital tufting enteropathy (DIAR5; 613217), Sivagnanam et al. (2008) identified homozygosity for a G-A transition at the donor splice site (c.491+1G-A) of exon 4 of the EPCAM gene in the affected individuals. The parents and an unaffected sib were heterozygous for the mutation, which was not detected in 400 controls, including 200 of Mexican American descent. RT-PCR analysis of patient duodenal tissue demonstrated a novel alternative splice form with deletion of exon 4. Western blot showed significantly decreased expression of EPCAM in intestinal tissue from 1 of the CTE patients, compared to 2 controls and 1 control patient with inflammatory bowel disease.
Schnell et al. (2013) studied the c.491+1G-A mutation, which was predicted to result in a deletion (Trp143_Thr164del). Functional analysis in HEK293T cells demonstrated that the mutant is retained in the endoplasmic reticulum (ER), causing loss of the cell surface localization observed with wildtype EPCAM.
In a 12-year-old native Canadian patient with congenital tufting enteropathy (DIAR5; 613217), Sivagnanam et al. (2008) identified homozygosity for a G-A transition at the acceptor splice site (c.427-1G-A) of exon 4 of the EPCAM gene. The mutation was not found in more than 170 North American control DNA samples.
Schnell et al. (2013) designated this EPCAM intron 3 mutation c.426-1G-A and predicted that it would result in a deletion (Trp143_Thr164del). Functional analysis in HEK293T cells demonstrated that the mutant is retained in the ER, causing loss of the cell surface localization observed with wildtype EPCAM.
In a 5-year-old Russian patient with congenital tufting enteropathy (DIAR5; 613217), Sivagnanam et al. (2008) identified heterozygosity for a c.200G-A transition in exon 3 of the EPCAM gene, predicted to cause a cys66-to-tyr (C66Y) substitution. The mutation was not found in more than 170 North American control DNA samples. Noting that most families reported with CTE are consanguineous or follow a pattern consistent with autosomal recessive inheritance, Sivagnanam et al. (2008) stated that although it was possible that CTE was transmitted in an autosomal dominant fashion in this patient, compound heterozygosity with a second mutation in an unsequenced noncoding region of the EPCAM gene was also possible.
Schnell et al. (2013) restudied the Russian patient with CTE/DIAR5 in whom Sivagnanam et al. (2008) originally detected only a heterozygous C66Y substitution, and identified an additional intronic mutation in the EPCAM gene (c.556-14A-G; 185535.0009), which was predicted to result in a premature termination codon (Tyr186PhefsTer6).
Schnell et al. (2013) designated the transition resulting in the C66Y substitution c.197G-A. By nonreducing PAGE analysis of transfected HEK293T cells, Schnell et al. (2013) found that EPCAM with the C66Y mutation formed a dimer. They hypothesized that, since C66 is normally engaged in a disulfide bond with C99, free C99 in mutant EPCAM may engage in intermolecular dimerization. The C66Y mutant was retained and degraded in the endoplasmic reticulum, causing loss of the cell surface localization observed with wildtype EPCAM. In immunostained transfected HEK293T cells, Schnell et al. (2013) also observed that the c.556-14A-G mutant was minimally detectable and was not present at the cell surface. Western blot analysis indicated that the truncated mutant is expressed, leading the authors to suggest that it is likely degraded.
In a patient born of first-cousin parents, who had congenital tufting enteropathy (DIAR5; 613217) and developed chronic inflammatory arthritis at 4 years of age, Al-Mayouf et al. (2009) identified homozygosity for a 1-bp insertion (c.498insC) in exon 5 of the EPCAM gene, causing a frameshift resulting in a premature termination codon (Gln167ProfsTer21).
In affected individuals from 4 unrelated consanguineous Kuwaiti families and 1 consanguineous Qatari family, who had severe neonatal diarrhea and typical tufting on intestinal biopsies, Salomon et al. (2011) identified homozygosity for the c.498insC mutation in the EPCAM gene. The mutation was not found in 119 ethnically matched controls. In 2 additional patients from unrelated Kuwaiti families, the c.498insC mutation was found in compound heterozygosity with a splice site mutation (185535.0008). Both mutations were predicted to truncate the C-terminal domain necessary for anchorage of EPCAM at the intercellular membrane, and immunohistochemistry of intestinal biopsies failed to detect EPCAM protein at this membrane. Haplotype analysis using microsatellite markers revealed that carriers of the c.498insC mutation shared a minimal common haplotype of 473 kb, consistent with a founder effect that occurred approximately 5,000 to 6,000 years earlier (190 generations removed) in this population.
In immunostained transfected HEK293T cells, Schnell et al. (2013) observed that the 498insC mutant was minimally detectable and was not present at the cell surface, in contrast to wildtype EPCAM. Western blot analysis indicated that the truncated mutant is expressed, leading the authors to suggest that it is likely degraded.
Salomon et al. (2014) noted that the c.498insC mutation is sometimes designated c.499dup.
In 4 Dutch families with colorectal cancer (LYNCH8; 613244) showing high microsatellite instability (MSI-high) and loss of MSH2 (609309) protein, but in which no mutations in MSH2 were found, Ligtenberg et al. (2009) detected a heterozygous 5-kb deletion encompassing the 2 most 3-prime exons of the TACSTD1 gene while leaving the promoter region of the MSH2 gene intact. Sequence analysis defined the deletion breakpoints with an intervening deletion of 4,909 bp, denoted 859-1462_*1999del, of the TACSTD1 cDNA. Haplotype analysis suggested that this mutation originated from a common founder. All 6 MSI-high tumors from these families showed methylation of the MSH2 promoter by methylation-specific PCR and subsequent bisulfite sequencing.
Chan et al. (2006) reported a family with inheritance, in 3 successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene (609309), without evidence of DNA mismatch repair gene mutation. Three sibs carrying the germline methylation developed early-onset colorectal or endometrial cancers (LYNCH8; 613244), all with microsatellite instability and MSH2 protein loss. The authors demonstrated different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. Although the underlying mechanism remained unclear, it was considered possible that the methylation is controlled by a genetic event associated with the disease haplotype.
Ligtenberg et al. (2009) analyzed the family reported by Chan et al. (2006) with heritable MSH2 promoter methylation and identified a heterozygous deletion of 22.8 kb (TACSTD1 cDNA, 555+894_*14194del) that segregated with the disease. The deletion extended from intron 5 of the TACSTD1 gene to approximately 2.4 kb upstream of MSH2, encompassing the 3-prime end of TACSTD1 and leaving the MSH2 promoter intact. Ligtenberg et al. (2009) identified the same mutation in another Chinese family; there was no evidence for a founder mutation. RT- and methylation-specific PCR of tissue samples from affected individuals showed that methylation of MSH2 was limited to TACSTD1-expressing cells.
In a female infant with congenital tufting enteropathy (DIAR5; 613217), Sivagnanam et al. (2010) identified homozygosity for a 412C-T transition in exon 3 of the EPCAM gene, resulting in an arg138-to-ter (R138X) substitution. The unaffected first-cousin parents of Pakistani descent were heterozygous for the mutation. Fluorescent immunohistochemical staining of duodenal biopsy tissue from the patient demonstrated markedly decreased EPCAM staining throughout the tissue sample compared to control.
In immunostained transfected HEK293T cells, Schnell et al. (2013) observed that the R138X mutant was minimally detectable and was not present at the cell surface, in contrast to wildtype EPCAM. Western blot analysis indicated that the truncated mutant is expressed and secreted.
In a male patient with severe neonatal diarrhea and enterocyte tufting (DIAR5; 613217), from a consanguineous Kuwaiti family, Salomon et al. (2011) identified homozygosity for a -2A-G transition in intron 4 of the EPCAM gene (IVS4-2A-G), which was not found in 119 ethnically matched controls. Sequencing of RT-PCR products demonstrated that the splice site mutation caused abnormal skipping of exon 5. In 2 additional patients from unrelated Kuwaiti families, the IVS4-2A-G mutation was found in compound heterozygosity with a recurrent c.498insC mutation (185535.0004). Both mutations were predicted to truncate the C-terminal domain necessary for anchorage of EPCAM at the intercellular membrane, and immunohistochemistry of intestinal biopsies failed to detect EPCAM protein at this membrane. Haplotype analysis using microsatellite markers showed that a common haplotype of more than 14.1 Mb segregated with the IVS4-2A-G mutation, suggesting a founder effect that occurred less than 40 generations earlier in this population.
Schnell et al. (2013) studied the IVS4 EPCAM mutant, which they designated c.492-2A-G and which was predicted to result in premature termination (Ala165MetfsTer24). In immunostained transfected HEK293T cells, the c.492-2A-G mutant was minimally detectable and was not present at the cell surface, in contrast to wildtype EPCAM. Western blot analysis indicated that the truncated mutant is expressed, leading the authors to suggest that it is likely degraded.
For discussion of the splice site mutation in the EPCAM gene (c.556-14A-G) that was found in compound heterozygous state in a patient with congenital tufting enteropathy (DIAR5; 613217) by Schnell et al. (2013), see 185535.0003.
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