Alternative titles; symbols
HGNC Approved Gene Symbol: CDH1
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:68,737,292-68,835,537 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | {Prostate cancer, susceptibility to} | 176807 | Autosomal dominant; Somatic mutation; X-linked | 3 |
| Blepharocheilodontic syndrome 1 | 119580 | Autosomal dominant | 3 | |
| Breast cancer, lobular, somatic | 114480 | 3 | ||
| Diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate | 137215 | Autosomal dominant | 3 | |
| Endometrial carcinoma, somatic | 608089 | 3 | ||
| Ovarian cancer, somatic | 167000 | 3 |
The CDH1 gene encodes E-cadherin, a calcium ion-dependent cell adhesion molecule that functions in the establishment and maintenance of epithelial cell morphology during embryogenesis and adulthood (summary by Riethmacher et al., 1995).
Mansouri et al. (1987) examined the amino acid sequence of uvomorulin and concluded that the gene is highly conserved. Sequence comparison showed extensive similarity to chicken LCAM. Using the mouse cDNA clone, Mansouri et al. (1987) screened a human liver cDNA library and isolated a 2-kb cDNA clone containing coding sequences for uvomorulin. Sequence comparison showed over 80% identity to the mouse in both nucleotide and amino acid sequences.
In postimplantation embryos and in adult tissues of mice, uvomorulin is exclusively expressed in epithelial cells. In adult intestinal epithelial cells, Boller et al. (1985) found that uvomorulin is concentrated in the intermediate junctions.
Berx et al. (1995) cloned the human E-cadherin gene and showed that it has 16 exons spanning approximately 100 kb of genomic DNA. The gene structure is similar to that of other cadherins.
By Southern blot analysis of DNA from a panel of mouse-human somatic cell hybrids, Mansouri et al. (1987, 1988) assigned the UVO gene to chromosome 16q (16p11-qter). In the mouse the Um locus is on chromosome 8 (Mansouri et al., 1987; Eistetter et al., 1988), together with a number of other loci that are located on human 16q (Scherer et al., 1989).
Using a cDNA probe for the human UVO gene, Natt et al. (1989) performed Southern blot analysis of 2 overlapping interstitial deletions on human chromosome 16q and thereby assigned the UVO locus to 16q22.1, distal to LCAT (606967) and proximal to HP (140100) and TAT (613018). Chen et al. (1991) confirmed the assignment to chromosome 16 and concluded that UVO is located near LCAT in band 16q22.1. Starting with a human-hamster cell hybrid carrying a single copy of chromosome 16 as the only human genetic material, Ceccherini et al. (1992) generated radiation hybrids retaining unselected fragments of this human chromosome. The most likely order and location of 38 DNA sequences including the UVO gene and the TAT gene were established by multiple pairwise analysis and scaled to estimate the physical distance in megabases. The experiments illustrated the usefulness of radiation hybrids for mapping. Berx et al. (1995) confirmed the map position of CDH1 to 16q22.1 by fluorescence in situ hybridization.
Nuclear Magnetic Resonance Spectroscopy
Overduin et al. (1995) determined the 3-dimensional structure of the amino-terminal repeat of mouse epithelial cadherin using multidimensional heteronuclear magnetic resonance spectroscopy. Unexpected structural similarities with the immunoglobulin fold suggested an evolutionary relation between the calcium-dependent cadherin cell adhesion molecules and the calcium-independent immunoglobulin cell adhesion molecules.
Crystal Structure
Boggon et al. (2002) presented the 3.1-angstrom resolution crystal structure of the whole, functional extracellular domain from C-cadherin, a representative classical cadherin from Xenopus. The structure suggested a molecular mechanism for adhesion between cells by classical cadherins, and it provided a new framework for understanding both same-cell (cis) and juxtaposed-cell (trans) cadherin interactions.
Cryoelectron Tomography
Al-Amoudi et al. (2007) applied cryoelectron tomography of vitreous sections from human epidermis to visualize the 3-dimensional molecular architecture of desmosomal cadherins at close-to-native conditions. The 3-dimensional reconstructions showed a regular array of densities at approximately 70-angstrom intervals along the midline, with a curved shape resembling the x-ray structure of C-cadherin, a representative classical cadherin. Model-independent 3-dimensional image processing of extracted subtomograms revealed the cadherin organization. After fitting the C-cadherin atomic structure into the averaged subtomograms, Al-Amoudi et al. (2007) saw a periodic arrangement of a trans W-like and a cis V-like interaction corresponding to molecules from opposing membranes and the same cell membrane, respectively.
Cano et al. (2000) found that transcription of mouse E-cadherin is under the control of Snail (SNAI1; 604238), a strong repressor that specifically interacts with the mouse E-cadherin promoter. By in situ hybridization of early mouse embryos undergoing epithelial-mesenchymal transitions, they found expression of E-cadherin to be inversely correlated with expression of Snai1. Cano et al. (2000) found strong evidence that abnormal expression of SNAI1 could also underlie the tumorigenic conversion of epithelia associated with the loss of E-cadherin expression. In a screen of several mouse cell lines, they detected high expression of Snai1 mRNA, and low expression of E-cadherin mRNA, in cell types that are highly invasive and metastatic, whereas the opposite pattern was found in noninvasive epithelial cell lines. They found the same inverse correlation between SNAI1 and E-cadherin expression in human carcinoma cell lines of various etiologies, as well as in primary human tumors undergoing malignant progression. Only a human bladder transitional cell carcinoma cell line, which downregulates E-cadherin through hypermethylation of the E-cadherin promoter, did not show high SNAI1 expression. By transfection experiments with several epithelial cell lines, Cano et al. (2000) found that Snai1 overexpression leads to a dramatic conversion to a fibroblastic phenotype at the same time that E-cadherin expression is lost and tumorigenic and invasive properties are acquired.
Batlle et al. (2000) found the identical inverse pattern of Snai1 and E-cadherin expression by Northern blot analysis of a panel of epithelial tumor cell lines. Likewise, they also found that exogenous expression of SNAI1 downregulates E-cadherin mRNA. In addition, Batlle et al. (2000) found that reduction in SNAI1 levels by transfection of antisense SNAI1 promotes a significant restoration of E-cadherin mRNA and protein. Through mutation analysis and gel retardation assays, Batlle et al. (2000) found that the 3 E-boxes contained in the promoter region of E-cadherin cooperate in SNAI1-mediated E-cadherin repression.
Using retroviral transduction, Palmer et al. (2004) generated human SW480-ADH colon cancer cells that ectopically express mouse hemagglutinin-tagged protein (SNAIL-HA). Overexpression of Snai1 in these cells resulted in lower vitamin D receptor (VDR; 601769) mRNA and protein expression and inhibited induction of E-cadherin and VDR by 1,25(OH)2D3. A 1,25(OH)2D3 analog inhibited tumor growth in immunodeficient mice injected with mock cells, but not in those injected with SNAIL-HA cells. In 32 paired samples of normal colon and tumor tissue from patients undergoing colorectal surgery, Palmer et al. (2004) found that high SNAI1 expression in tumor tissue correlated with downregulation of VDR and E-cadherin (p = 0.007 and 0.0073, respectively). Palmer et al. (2004) concluded that the balance between VDR and SNAI1 expression is critical for E-cadherin expression, which influences cell fate during colon cancer progression.
Jamal and Schneider (2002) found downregulation of E-cadherin and associated catenin proteins in human melanocytes and melanoma cells following ultraviolet induction of endothelin-1 (EDN1; 131240) through the type B endothelin receptor (EDNRB; 131244). Downregulation of E-cadherin through this pathway involved the downstream activation of caspase-8 (601763), but not the distal executioner caspases, and it did not lead to apoptosis. EDN1 also induced a transient association between caspase-8 and E-cadherin/beta-catenin (CTNNB1; 116806) complexes. Jamal and Schneider (2002) concluded that inhibition of E-cadherin through this pathway would tend to promote melanoma invasion.
Listeria monocytogenes is the etiologic agent of listeriosis, a severe human food-borne infection characterized by bacterial dissemination to the central nervous system and the fetoplacental unit, due to its capacity to cross the intestinal barrier, the blood-brain barrier, and the fetoplacental barrier (Lorber, 1997). An important feature of this bacterium is its ability to induce its own internalization into cells that normally are nonphagocytic, such as epithelial cells. Internalin A (InlA) and InlB, 2 leucine-rich repeat invasion proteins that have been characterized in detail, mediate entry into different cell types. Human E-cadherin promotes entry of Listeria monocytogenes into mammalian cells by interacting with the bacterial surface protein InlA. Lecuit et al. (1999) showed that mouse E-cadherin, although very similar to human E-cadherin (85% identical), is not a receptor for internalin. By a series of domain-swapping and mutagenesis experiments, they identified pro16 of E-cadherin as a residue critical for specificity: a pro-to-glu substitution in human E-cadherin totally abrogated interaction, whereas a glu-to-pro substitution in mouse E-cadherin resulted in a complete gain of function. A correlation between cell permissivity and the nature of residue 16 in E-cadherins from several species was established. The location of this key specificity residue in a region of E-cadherin not involved in cell-cell adhesion and the stringency of the interaction demonstrated by Lecuit et al. (1999) have important consequences not only for the understanding of internalin function but also for the choice of the animal model to be used to study human listeriosis: mouse, albeit previously widely used, and rat appear as inappropriate animal models to study all aspects of human listeriosis, as opposed to guinea pig, which stands as a small animal of choice for future in vivo studies.
E-cadherin also has a role in food-borne infection with Listeria monocytogenes. This pathogen expresses a surface protein, internalin, that interacts with the host receptor, E-cadherin, to promote entry into human epithelial cells. Murine E-cadherin, in contrast to guinea pig E-cadherin, does not interact with internalin, excluding the mouse as a model for addressing internalin function in vivo. Lecuit et al. (2001) demonstrated that in guinea pigs and transgenic mice expressing human E-cadherin, internalin mediates invasion of enterocytes and crossing of the intestinal barrier.
Kawasaki et al. (2003) showed that overexpression of ASEF (605216) decreases E-cadherin-mediated cell-cell adhesion and promotes the migration of epithelial canine kidney cells. Both of these activities were stimulated by truncated APC (611731) proteins expressed in colorectal tumor cells. Experiments based on RNA interference and dominant-negative mutants showed that both ASEF and mutated APC are required for the migration of colorectal tumor cells expressing truncated APC. Kawasaki et al. (2003) concluded that the APC-ASEF complex functions in cell migration as well as in E-cadherin-mediated cell-cell adhesion, and that truncated APC present in colorectal tumor cells contributes to their aberrant migratory properties.
The morphogenesis of organs as diverse as lungs, teeth, and hair follicles is initiated by a downgrowth from a layer of epithelial stem cells. During follicular morphogenesis, stem cells form this bud structure by changing their polarity and cell-cell contact. Jamora et al. (2003) showed that this process is achieved through simultaneous receipt of 2 external signals: a WNT protein (WNT3A; 606359) to stabilize beta-catenin, and a bone morphogenetic protein inhibitor (Noggin; 602991) to produce Lef1 (153245). Beta-catenin binds to and activates Lef1 transcription complexes that appear to act uncharacteristically by downregulating the gene encoding E-cadherin, an important component of polarity and intercellular adhesion. When either signal is missing, functional Lef1 complexes are not made, and E-cadherin downregulation and follicle morphogenesis are impaired. In Drosophila, E-cadherin can influence the plane of cell division and cytoskeletal dynamics. Consistent with this notion, Jamora et al. (2003) showed that forced elevation of E-cadherin levels block invagination and follicle production. Jamora et al. (2003) concluded that their findings reveal an intricate molecular program that links 2 extracellular signaling pathways to the formation of a nuclear transcription factor that acts on target genes to remodel cellular junctions and permit follicle formation.
Kawasaki and Taira (2004) presented evidence that short interfering RNAs (siRNAs) targeted to CpG islands of an E-cadherin promoter induced DNA and histone methylation and repressed transcription of the E-cadherin gene. A retraction was published.
Hayashi and Carthew (2004) investigated the physical basis of biologic patterning of the Drosophila retina in vivo. They demonstrated that E-cadherin and N-cadherin (CDH2; 114020) mediate apical adhesion between retina and epithelia cells. Differential expression of N-cadherin within a subgroup of retinal cells (cone cells) caused them to form an overall shape that minimized their surface contact with surrounding cells. The cells within this group, in both normal and experimentally manipulated conditions, packed together in the same way as soap bubbles do. The shaping of cone cell group and packing of its components precisely imitated the physical tendency for surfaces to be minimized. Hayashi and Carthew (2004) concluded that simple patterned expression of N-cadherin resulted in a complex spatial pattern of cells owing to cellular surface mechanics.
Ino et al. (2002) demonstrated that dysadherin (606669) posttranslationally downregulates E-cadherin, the prime mediator of cell-cell adhesion in epithelial cells. Sato et al. (2003) demonstrated that dysadherin expression was significantly negatively correlated with E-cadherin expression in thyroid carcinomas.
Full-length membrane-bound E-cadherin is cleaved in the extracellular domain by a metalloprotease, generating a 38-kD C-terminal fragment, which can be further processed by a gamma-secretase-like activity into a soluble 33-kD C-terminal fragment. Using a panel of mouse embryonic fibroblasts deficient in various metalloproteases, Maretzky et al. (2005) found that those cells deficient in Adam10 (602192) showed reduced generation of the E-cadherin 38-kD C-terminal fragment. They further found that Adam10 was responsible for both constitutive and regulated E-cadherin shedding in mouse fibroblasts and keratinocytes. Adam10-mediated E-cadherin shedding affected epithelial cell-cell adhesion as well as cell migration, and it modulated beta-catenin subcellular localization and downstream signaling.
Pena et al. (2005) studied the expression and functional correlation of the SNAI1, CDH1, vitamin D receptor (VDR; 601769), and ZEB1 (189909) genes and examined their possible involvement in colon cancer. Their expression was measured by real-time PCR in 114 patients with colorectal cancer, and tumor characteristics were analyzed in each patient. SNAI1 expression was associated with downregulation of CDH1 (P = less than 0.001) and VDR (P = less than 0.001) gene products. There was a positive correlation between CDH1 and VDR expressions, but the association between SNAI1 and CDH1 was not found in patients with high expression of ZEB1. There was a correlation between downregulation of: (a) ZEB1 and presence of polyps in surgical resections; (b) VDR and poor differentiation; and (c) CDH1 and poor differentiation, vascular invasion, presence of lymph node metastases and advanced stages; as well as a trend toward a correlation between SNAI1 expression in tumors and vascular invasion. Pena et al. (2005) suggested analyzing these genes in colon cancer patients for prognostic purposes and for predicting response to possible therapies with vitamin D or its analogs.
Frebourg et al. (2006) found that in human embryos CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence and at 6 weeks in the lateral and medial nasal prominences, and is therefore expressed during critical stages of lip and palate development. These results were in agreement with those obtained by Montenegro et al. (2000) in mouse embryos by immunohistochemistry. Frebourg et al. (2006) also found that at most time points examined CDH1 expression varied with that of PVRL1 (600644), mutations in which cause autosomal recessive clefting syndromes with ectodermal dysplasia (see 225060).
By in silico analysis, Place et al. (2008) identified putative miR373 (MIRN373; 611954) target sites in the promoter regions of the E-cadherin and cold shock domain-containing C2 (CSDC2; 617689) genes. Transfection of miR373 and its precursor hairpin into PC-3 human prostate carcinoma cells induced expression of E-cadherin and CSDC2. Knockdown experiments confirmed that induction of E-cadherin by pre-miR373 required the miRNA-processing enzyme Dicer (606241). Enrichment of RNA polymerase II (see 180660) was detected at both E-cadherin and CSDC3 promoters after miR373 transfection. Induction of E-cadherin and CSDC2 by miR373 was not observed in several other human cell lines of different tissue origins, indicating that miR373 differentially activates target genes in different cell lines.
Cavey et al. (2008) focused on Drosophila homophilic E-cadherin complexes rather than total E-cadherin, including diffusing 'free' E-cadherin, because these complexes are a better proxy for adhesion. They found that E-cadherin complexes partition in very stable microdomains (i.e., bona fide adhesive foci, which are more stable than remodeling contacts). Stability and mobility of these microdomains was dependent on 2 actin populations: small stable actin patches concentrated at homophilic E-cadherin clusters and a dynamic contractile actin network that constrains homophilic E-cadherin clusters lateral movement by a tethering mechanism. Alpha-catenin controls epithelial architecture mainly through regulation of the mobility of homophilic E-cadherin clusters and was largely dispensable for their stability. Uncoupling stability and mobility of E-cadherin complexes suggested that stable epithelia may remodel through the regulated mobility of very stable adhesive foci.
Among 48 primary ovarian cancer (167000) tumors and corresponding metastases, Blechschmidt et al. (2008) found a significant association (p = 0.008) between reduced E-cadherin expression in the primary cancer tissue and shorter overall survival. Patients with decreased E-cadherin expression and increased SNAIL expression in the primary tumor showed a higher risk of death (p = 0.002). There was no significant difference in expression of E-cadherin or SNAIL between primary tumors and metastases. The findings were consistent with a role for E-cadherin and SNAIL in the behavior of metastatic cancer.
Pinho et al. (2009) demonstrated that wildtype E-cadherin regulated MGAT3 (604621) gene transcription, resulting in increased N-acetylglucosaminyltransferase III (GnT-III) expression. GnT-III and N-acetylglucosaminyltransferase V (GnT-V, or MGAT5, 601774) competitively modified E-cadherin N-glycans. RNAi-knockdown of GnT-III in MCF-7/AZ cells revealed membrane delocalization of E-cadherin leading to its cytoplasmic accumulation. Further, GnT-III knockdown in cells also caused modifications of E-cadherin N-glycans catalyzed by GnT-III and GnT-V. Pinho et al. (2009) proposed a bidirectional crosstalk between E-cadherin and GnT-III/GnT-V, which may influence tumor progression and metastasis.
Banh et al. (2009) showed that the first 2 extracellular domains of N-cadherin interacted with the inhibitory receptor KLRG1 (604874), blocked interaction of KLRG1 with E-cadherin, and could regulate KLRG1 signaling. Binding of KLRG1 to E-cadherin inhibited E-cadherin-dependent cell adhesion and led to tyrosine phosphorylation of E-cadherin. The KLRG1/E-cadherin interaction led to the generation of a bidirectional signal in which both KLRG1 and E-cadherin activated downstream signaling cascades simultaneously, regulating cells expressing one or the other molecule.
Ma et al. (2010) found that MIR9 (see MIR9-3; 611188) directly downregulated CDH1 expression via an MIR9-binding site in the 3-prime UTR of the CDH1 transcript. Downregulation of CDH1 was required for MIR9-induced motility and invasiveness in human breast cancer cell lines. Downregulation of CDH1 via MIR9 also increased beta-catenin activity and VEGFA (192240) activity and secretion. Expression of MIR9 in nonmetastatic breast cancer cells induced angiogenesis, mesenchymal traits, and formation of metastases following injection in mice. Chromatin immunoprecipitation analysis revealed that both MYC (190080) and MYCN (164840) bound directly to the promoter region of the MIR9-3 gene and activated MIR9-3 transcription. Although MYC and MYCN also bound the MIR9-1 (611186) and MIR9-2 (611187) genes, MIR9-1 and MIR9-2 were less responsive than MIR9-3 to transcriptional activation by MYC and MYCN.
Maitre et al. (2012) showed that cell adhesion and cortex tension have different mechanical functions in controlling progenitor cell-cell contact formation and sorting during zebrafish gastrulation. Cortex tension controls cell-cell contact expansion by modulating interfacial tension at the contact. By contrast, adhesion has little direct function in contact expansion, but instead is needed to mechanically couple the cortices of adhering cells at their contacts, allowing cortex tension to control contact expansion. The coupling function of adhesion is mediated by E-cadherin and limited by the mechanical anchoring of E-cadherin to the cortex. Thus, Maitre et al. (2012) concluded that cell adhesion provides the mechanical scaffold for cell cortex tension to drive cell sorting during gastrulation.
Pan et al. (2015) found that G9A (EHMT2; 604599) expression was unregulated in human pancreatic cancer cells and that upregulation of G9A increased methylation of H3K9 and H3K27 on the promoter of E-cadherin to downregulate its expression. Specifically, G9A bound directly to the promoter of PCL3 (PHF19; 609740), a component of polycomb repressive complex-2 (PRC2), and increased PCL3 expression. By increasing PCL3 expression, G9A increased recruitment of PRC2 to the E-cadherin promoter to downregulate its expression by repressing expression of KDM7A (619640). Bioinformatic analysis and in vivo study with mice supported these results and indicated that G9A likely orchestrated PCL3 and KDM7A to inhibit E-cadherin in pancreatic cancer.
Diffuse Gastric and Lobular Breast Cancer Syndrome
Diffuse gastric and lobular breast cancer syndrome (DGLBC; 137215) is a predisposition cancer syndrome.
Striking examples of dominantly inherited predisposition to gastric cancer (including Napoleon Bonaparte's family) have been reported (Sokoloff, 1938). In addition, a number of dominantly inherited familial cancer syndromes are characterized by gastric cancer susceptibility. Guilford et al. (1998) reported heterozygous germline mutations in the CDH1 gene (192090.0005-192090.0007) in 3 kindreds of Maori origin from New Zealand with hereditary diffuse gastric cancer.
Richards et al. (1999) analyzed 8 UK kindreds with hereditary diffuse gastric cancer and identified novel germline CDH1 mutations (192090.0008 and 192090.0009) in 2 families. Both mutations were predicted to truncate the E-cadherin protein in the signal peptide domain. In 1 family, there was evidence of nonpenetrance and susceptibility to both gastric and colorectal cancer; thus, in addition to 6 cases of gastric cancer, a CDH1 mutation carrier developed colorectal cancer at age 30 years. Gayther et al. (1998) also described germline CDH1 mutations in familial gastric cancer. Yoon et al. (1999) screened 5 Korean patients with familial gastric cancer for germline mutations in the CDH1 gene and identified 2 with missense mutations.
To extend earlier observations of germline CDH1 mutations in kindreds with an inherited susceptibility to diffuse gastric cancer, Guilford et al. (1999) sought germline mutations in the CDH1 gene in 5 further families affected predominantly by diffuse gastric cancer and in 1 family with a history of diffuse gastric cancer and early-onset breast cancer. Heterozygous inactivating mutations were found in the CDH1 gene in each of these 6 families. No mutation hotspots were identified.
Aberrant promoter methylation and the associated loss of gene expression is a common finding in human cancers. Nevertheless, it had been difficult to demonstrate that methylation of a specific gene was causal in any given tumor and not a consequence of the malignant transformation. Grady et al. (2000) noted that patients with heterozygous germline mutations in the CDH1 gene develop gastric cancer, but their cancers consistently demonstrate no loss of heterozygosity (LOH) at the CDH1 locus. They hypothesized that methylation of the CDH1 promoter might represent the 'second genetic hit' in the genesis of these tumors. The CDH1 promoter was found to be consistently unmethylated in normal stomach mucosa, whereas 3 of 6 HDGC tumors with negative CDH1 staining had aberrant CDH1 promoter methylation. Two tumors that had retained unmethylated CDH1 promoters harbored somatic CDH1 mutations. No somatic mutations were found in 2 HDGC tumors showing CDH1 promoter methylation, but sequence polymorphisms confirmed that they retained a second wildtype allele. These findings indicated that the formation of HDGC tumors requires biallelic CDH1 inactivation, which in one-half of cases is accomplished by promoter methylation of a retained wildtype allele. Grady et al. (2000) pointed to examples of promoter methylation identified in sporadic cancers in which promoter methylation of the CDKN2A (600160) and RB1 (614041) genes had been noted, as well as in some renal tumors in patients with von Hippel-Lindau disease (193300).
Oliveira et al. (2002) performed germline CDH1 mutation screening in 39 kindreds with familial aggregation of gastric cancer, a subset of which fulfilled the criteria defined by the International Gastric Cancer Linkage Consortium (IGCLC) for hereditary diffuse gastric cancer. CDH1 germline mutations were detected in 4 of 11 (36.4%) HDGC families. No mutations were identified in 63.6% of HDGC families or in kindreds with familial aggregation of gastric cancer not fulfilling criteria for HDGC. These results added support to the evidence that only HDGC families harbor germline mutations in CDH1 and that genes other than CDH1 remained to be identified.
Humar et al. (2002) performed a germline mutation search in 10 gastric cancer families, 7 of which met the clinical criteria for HDGC. They identified germline mutations in 4 of the 7 families and in 1 family that was borderline for the clinical criteria. Of the mutations identified in the 5 families, 4 were previously unreported.
Suriano et al. (2003) screened a series of 66 young (diagnosed before age 50) gastric cancer probands for germline CDH1 mutations and identified 2 missense alterations: A617T (192090.0002) and A634V (192090.0015). Stably transfected cadherin-negative CHO cell lines were characterized in terms of aggregation, invasion, and motility. Cells expressing either the A634V or thr340-to-ala (T340A; 192090.0016) mutation failed to aggregate, showed invasive behavior, and migrated abnormally compared to wildtype cells in vitro. Cells expressing the A617T mutation displayed an intermediate ability to aggregate.
Suriano et al. (2003) characterized the effect of CDH1 germline missense mutations on the morphology, motility, and proliferation of transfected Chinese hamster ovary cells. Wildtype E-cadherin and A617T-expressing cells had an epithelial-like morphology, with polarized cells migrating unidirectionally. T340A- and A634V-expressing cells had a high-motility fibroblast-like phenotype, which was dependent on an increased level of active RhoA (165390). Val832-to-met (V832M; 192090.0017)-expressing cells grew in a piled-up structure of round cells, resulting from disturbance of binding between alpha-catenin (CTNNA1; 116805) and beta-catenin, and destabilization of the adhesion complex was shown to hamper the motile capabilities of these cells. CDH1 mutations showed no effect on cell proliferation. Suriano et al. (2003) concluded that the ability of cells expressing CDH1 mutations to invade is independent of their motile capabilities, providing evidence that motility is neither necessary nor sufficient for cells to invade.
Brooks-Wilson et al. (2004) ascertained 43 apparent cases of hereditary gastric cancer and screened them for germline CDH1 mutations. The authors identified heterozygosity in 10 different families for 10 loss-of-function mutations, including 2 insertions, 5 deletions, 2 splice-site substitutions, and 1 complex deletion/insertion involving a splice site. They also found 3 heterozygous missense mutations which were predicted to affect conserved residues and to have deleterious effects on protein function. Brooks-Wilson et al. (2004) noted that there were multiple cases of breast cancers, including pathologically confirmed lobular breast cancer (LBC; see 137215), in both mutation-positive and -negative families.
Masciari et al. (2007) identified a germline mutation in the CDH1 gene (192090.0021) in a woman who developed lobular breast cancer at age 42 years. The breast cancer was negative for E-cadherin by immunostaining, and further analysis detected loss of heterozygosity of part of the gene. The patient's mother reportedly developed lobular breast cancer at age 28. No other breast or gastric cancers were reported in the family.
Simoes-Correia et al. (2008) analyzed Chinese hamster ovary (CHO) cells stably expressing the germline E-cadherin R749W and E757K mutations, which are associated with hereditary diffuse gastric cancer, and observed an abnormal pattern of E-cadherin expression, with protein accumulating mainly in the endoplasmic reticulum (ER). The authors demonstrated that E-cadherin missense mutants are subject to ER quality control (ERQC) and undergo ER-associated degradation; treatment of these mutant cells with specific chemical chaperones restored E-cadherin to the cell membrane and rescued its function. Simoes-Correia et al. (2008) concluded that ERQC plays a major role in E-cadherin regulation.
Oliveira et al. (2009) reported 6 (6.5%) of 93 previously described mutation-negative hereditary diffuse gastric cancer probands who carried genomic deletions (see, e.g., 192090.0022 and 192090.0023) in the CDH1 gene. The statistically significant overrepresentation of Alu repeats around the breakpoints indicated nonallelic homologous recombination of Alu repeats as a likely mechanism for these deletions. When all mutations and deletions were considered, the overall frequency of CDH1 alterations in HDGC was approximately 46% (73 of 160), and large CDH1 deletions occurred in 3.8% of HDGC families.
Based on a literature review, Figueiredo et al. (2019) stated that inactivating mutations of CDH1 were found in 40% of families who met clinical criteria for HDGC. CDH1 mutation carriers have an estimated cumulative incidence of DGC of 70% for males and 56% for females by age 80 years. The probability of female carriers developing LBC is 42%. About 90% of invasive LBC display E-cadherin loss. Some cases of early-onset LBC in CDH1 mutation carriers occur in persons with no personal or family history of DGC. Figueiredo et al. (2019) stated that 23 different mutations were found to be associated with cleft lip/palate, 7 of which were found in families with DGC.
Blepharocheilodontic Syndrome 1
In 7 patients from 5 unrelated families with blepharocheilodontic syndrome (BCDS1; 119580), Ghoumid et al. (2017) identified heterozygosity for mutations in the CDH1 gene (see, e.g., 192090.0024-192090.0026). All of the variants involved highly conserved residues and were shown to affect E-cadherin expression and its subcellular localization.
In a Japanese girl with cleft lip and palate, choanal atresia, tetralogy of Fallot, and a neural tube defect, Nishi et al. (2016) identified heterozygosity for a missense mutation in the CDH1 gene (D676E; 192090.0027). Ghoumid et al. (2017) noted that this patient also exhibited eyelid anomalies characteristic of BCDS.
Based on a literature review, Figueiredo et al. (2019) noted that mutations in the CDH1 gene in patients with BCDS1 occur in the extracellular domain, possibly interfering with the ability of the protein to homodimerize and, consequently, interfering with its adhesive function.
Prostate Cancer, Susceptibility to
Jonsson et al. (2004) demonstrated an association between the -160C/A promoter polymorphism of CDH1 (192090.0018) and risk of hereditary prostate cancer.
Somatic Mutations
Reduced expression of E-cadherin is regarded as one of the main molecular events involved in dysfunction of the cell-cell adhesion system, triggering cancer invasion and metastasis. Becker et al. (1994) suggested that E-cadherin mutations contribute to the histopathologic appearance of stomach cancer because 13 of 26 diffuse gastric carcinomas (137215), which have reduced homophilic cell-to-cell interactions, had abnormal gene transcripts that were not seen in noncancerous tissue from the same patients, indicating a somatic origin.
Oda et al. (1994) analyzed 10 human cancer cell lines that showed growth characterized morphologically by loose cell-cell adhesion for possible structural abnormalities in the expressed E-cadherin. Strong mRNA and protein expression with no nucleotide sequence abnormalities was found in 4 cell lines, and mRNA was absent in 4 other cell lines. In the remaining 2 gastric carcinoma cell lines, the mRNA sequence was abnormal. One showed a 12-bp in-frame deletion with strong expression of mRNA and protein. In the other, there were 4 mRNA species with insertions of different sizes, among which the major transcripts (with a 7-bp insertion) caused a frameshift, and expression of both mRNA and protein were markedly reduced. In these 2 cell lines, DNA mutations were detected around exon-intron junctions, revealing that aberrant RNA splicing was the cause of the mRNA abnormalities. In addition, the wildtype allele of the E-cadherin locus was lost, suggesting that the E-cadherin gene had been inactivated by 2 hits (mutation and allele loss), similar to the mechanism for inactivation of tumor suppressor genes.
Risinger et al. (1994) identified somatic mutations in the CDH1 gene (see, e.g., 192090.0001-192090.0003) in carcinomas of the endometrium (608089) and ovary (167000). Two tumors had retention of the wildtype alleles, and 2 had somatic loss of heterozygosity in the tumor tissue. The findings were consistent with CDH1 acting as a tumor suppressor gene.
To investigate the molecular basis of altered CDH1 expression in cancer, Berx et al. (1995) performed a PCR/SSCP mutation screen of the CDH1 gene in 49 breast cancer patients. No relevant DNA changes were encountered in any of 42 infiltrative ductal or medullary breast carcinoma samples. In contrast, 4 of 7 infiltrative lobular breast carcinomas (see 137215) harbored protein truncation mutations (3 nonsense and 1 frameshift) in the extracellular part of the E-cadherin protein (e.g., 192090.0004). Each of the 4 lobular carcinomas with E-cadherin mutations showed tumor-specific loss of heterozygosity of chromosomal region 16q22.1 containing the E-cadherin locus, thus supporting the Knudson 2-hit hypothesis. Berx et al. (1995) detected no E-cadherin expression in these 4 tumors by immunohistochemistry.
Ilyas et al. (1997) concluded that mutations in CDH1 do not account for decreased E-cadherin protein expression in colorectal tumors. They found no association between either CDH1 allele loss or exon 16 replication errors and low levels of CDH1 protein expression in 54 sporadic colorectal cancers (114500) and 14 ulcerative colitis-associated colorectal cancers. The authors had postulated that CDH1 gene mutation or allele loss would affect E-cadherin's function as a suppressor of tumor invasion.
Berx et al. (1998) found reports of 69 somatic mutations of the CDH1 gene. These comprised, in addition to a few missense mutations, mainly splice site mutations and truncation mutations caused by insertions, deletions, and nonsense mutations. There was a major difference in mutation type between diffuse gastric and infiltrative lobular breast cancers. In diffuse gastric tumors, the predominant defects were exon skippings, which caused in-frame deletions. By contrast, most mutations found in infiltrating lobular breast cancers were out-of-frame mutations, which were predicted to yield secreted truncated E-cadherin fragments. In most cases these mutations occurred in combination with loss of heterozygosity.
Wheeler et al. (2002) examined the possible contribution of E-cadherin to sporadic small intestinal adenocarcinoma. E-cadherin protein expression was assessed immunohistochemically in a total of 21 nonfamilial, nonampullary small intestinal adenocarcinomas. Eight tumors (38%) had decreased protein expression at the cell membrane, a finding in common with colorectal carcinomas (Ilyas et al., 1997). This led the authors to suggest that mutation or promoter hypermethylation in the E-cadherin gene may play an important role in the pathogenesis of sporadic small intestinal adenocarcinoma.
Deplazes et al. (2009) demonstrated that E-cadherin harboring an in-frame deletion of exon 8 had reduced ability to activate Rac1 (602048) and to inhibit Rho (165390). The lack of Rac1 activation influenced the downstream signaling of Rac1, as shown by a decrease in the binding of the Rac1 effector protein IQGAP1 (603379) to Rac1-GTP. Reduced membranous localization of p120-catenin (CTNND1; 601045) in mutant E-cadherin expressing cells was associated with the lack of negative regulation of Rho by mutant E-cadherin. The enhanced motility and invasion associated with mutant E-cadherin was sensitive to the inhibition of Rac1 and Rho. Deplazes et al. (2009) concluded that the mutation of E-cadherin had a reciprocal influence on Rac1 and Rho activation, and that Rac1 and Rho are involved in the establishment of the migratory and invasive phenotype of tumor cells harboring an E-cadherin mutation.
Frebourg et al. (2006) reported the association of CDH1 mutations with cleft lip with or without cleft palate (119530) in 2 families with hereditary diffuse gastric cancer. In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant-negative effects. Expression of CDH1 in human embryos during critical stages of lip and palate development suggested that alteration of the E-cadherin pathway may contribute to human clefting. The development of diffuse gastric cancer in CDH1 mutation carriers requires the somatic inactivation of the wildtype allele (Grady et al., 2000; Oliveira et al., 2004), as predicted by the Knudson 2-hit model.
Riethmacher et al. (1995) introduced a targeted mutation into the E-cadherin gene by homologous recombination in mouse embryonic stem cells. The mutation removed E-cadherin sequences essential for Ca(2+) binding and for adhesive function. These embryonic stem cells were used to generate mice carrying the mutation. Heterozygous mutant animals appeared normal and were fertile. However, the homozygous mutation was not compatible with life; the homozygous embryos showed severe abnormalities before implantation. Particularly, the adhesive cells of the morula dissociated shortly after compaction had occurred, and their morphologic polarization was then destroyed.
Development of malignant tumors is in part characterized by the ability of a tumor cell to overcome cell-cell adhesion and to invade surrounding tissue. E-cadherin, the main adhesion molecule of epithelia, has been implicated in carcinogenesis because it is frequently lost in human epithelial cancers. Reestablishing the functional cadherin complex in tumor cell lines results in reversion from an invasive to a benign epithelial phenotype. Perl et al. (1998) found that loss of E-cadherin expression coincides with the transition from well-differentiated adenoma to invasive carcinoma in a transgenic mouse model of pancreatic beta-cell carcinogenesis. Intercrossing model mice with transgenic mice that maintained E-cadherin expression in beta-tumor cells resulted in arrest of tumor development at the adenoma stage, whereas expression of a dominant-negative form of E-cadherin induced early invasion and metastasis. The results demonstrated that loss of E-cadherin-mediated cell adhesion is a rate-limiting step in the progression from adenoma to carcinoma and is a cause of that progression, not a consequence.
The liver cell adhesion molecule is a primary cell adhesion molecule that appears in a distinct pattern at a variety of inductive embryonic sites as well as in adult tissues. It was initially isolated on the basis of its ability to mediate calcium-dependent adhesion between cells of the chicken liver epithelium. Gallin et al. (1987) isolated and determined the nucleic acid sequence of a cDNA clone encoding chicken LCAM. The predicted sequence of the protein supported an earlier conclusion that LCAM is an intrinsic membrane protein. Its sequence was not homologous to other known protein sequences, including those of the neural cell adhesion molecule (NCAM; 116930) and other members of the immunoglobulin superfamily. It was not certain that the liver cell adhesion molecule of the chicken is different from calcium-dependent adhesion molecules, including uvomorulin and E-cadherin, which have been isolated from different epithelial tissues or cell lines in mammals; these molecules have biochemical properties and tissue distributions so similar to those of LCAM that it is likely that all of them are its mammalian homologs.
In an endometrial carcinoma (608089), Risinger et al. (1994) identified a somatic C-to-G transversion in the CDH1 gene, resulting in a leu711-to-val (L711V) substitution. The wildtype allele was not lost.
Endometrial Carcinoma, Somatic
In an endometrial carcinoma (608089), Risinger et al. (1994) identified a somatic G-to-A transition in the CDH1 gene, resulting in an ala617-to-thr (A617T) substitution. Somatic loss of heterozygosity was identified in the tumor tissue.
Diffuse Gastric and Lobular Breast Cancer Syndrome
Suriano et al. (2003) detected a heterozygous germline A617T mutation in 2 African American female patients with diffuse gastric cancer (DGLBC; 137215). The authors observed that CHO cells expressing the A617T mutation displayed decreased cell-to-cell aggregation.
In ovarian carcinoma tissue (167000), Risinger et al. (1994) identified a somatic A-to-G transition in codon 838 of the CDH1 gene, resulting in a ser838-to-gly (S838G) substitution. The tumor tissue showed somatic loss of heterozygosity.
In an infiltrative lobular breast carcinoma (LBC; see 137215), Berx et al. (1995) found a somatic GAA (glu)-to-TAA (stop) nonsense mutation (E261X) in the CDH1 gene. Tumor-specific loss of heterozygosity of chromosomal region 16q22.1 was demonstrated in this case.
In affected members of a Maori family from New Zealand with early-onset diffuse gastric cancer (DGLBC; 137215) originally reported by Jones (1964), Guilford et al. (1998) identified a heterozygous 1008G-T transversion in the CDH1 gene. The G-to-T transversion was in the last nucleotide (position 1008) of exon 7, which is part of the donor splice consensus sequence. RT-PCR studies showed that the mutation resulted in a 7-bp insertion derived from the intronic sequence between the normal splice donor site and an adjacent cryptic splice site, and was predicted to generate a premature stop codon in exon 8 of the CDH1 gene. The cryptic splicing of the 1008T transcript occurred with high efficiency; only 1 of 20 clones derived from the normal 180-bp PCR product contained the 1008T mutation. Alternatively, the G-to-A transversion could have resulted in a glu336-to-asp (E336D) substitution, which could have had important effects on the correct functioning of the protein. In this family, the age of death from gastric cancer ranged upward from 14 years, with the majority of cases occurring in people under the age of 40. The pedigree pattern was consistent with dominant inheritance of a susceptibility gene with incomplete penetrance. The presence of a somatic mutation at position 1008 of the CDH1 gene had been reported in a sporadic case of histologically diffuse gastric carcinoma (Oda et al., 1994).
Guilford et al. (1998) described a family in which multiple members with diffuse gastric cancer (DGLBC; 137215) were heterozygous for the insertion of an additional C residue in a run of 5 cytosines at positions 2382 to 2386. The resulting frameshift led to an E-cadherin molecule lacking about half of its cytoplasmic domain. The gastric cancer was of the early-onset, histologically diffuse type.
In a family with early-onset, histologically diffuse gastric cancer (DGLBC; 137215), Guilford et al. (1998) found that the 30-year-old proband was heterozygous for a 2095C-T transition in the CDH1 gene, resulting in a gln699-to-ter (Q699X) substitution. The mutation was predicted to result in an E-cadherin peptide lacking both the transmembrane and cytoplasmic domains.
In a family from the UK in which 6 members had gastric cancer (DGLBC; 137215), Richards et al. (1999) identified a splice acceptor site mutation, an A-to-G transition at position -2 from nucleotide 49 at the start of exon 2 of the CDH1 gene. In addition to the 6 members with gastric cancer, 1 member of the family developed adenocarcinoma of the rectum at the age of 30 years.
In a family from the UK with 3 cases of gastric cancer (DGBLC; 137215) in successive generations, diagnosed at ages 27, 50, and 38 years, Richards et al. (1999) identified a germline G-to-A transition at nucleotide 59 in exon 2 of the CDH1 gene, resulting in a trp20-to-ter (W20X) substitution. The mutation was predicted to truncate the E-cadherin gene product in the signal peptide domain, which is cleaved from the N terminus of the mature protein.
In a family in which multiple members had diffuse gastric cancer (DGLBC; 137215), Guilford et al. (1999) identified a heterozygous G-to-T transversion at nucleotide 70 in exon 2 of the CDH1 gene, resulting in a glu24-to-ter (Q24X) substitution in the signal peptide of the E-cadherin precursor protein. Lynch et al. (2000) described E-cadherin mutation-based genetic counseling in this kindred. Of 24 family members tested for the 70G-T mutation, 9 were found to be positive and 15 negative. None of the 19 patients counseled wanted results sent to their physicians once they recognized the potential for insurance discrimination. None had undergone endoscopic ultrasound. Three who were positive for the mutation expressed strong interest in prophylactic gastrectomy. Three of the 9 who tested positive were affected and had died by the time of report.
In a family segregating diffuse gastric cancer (DGLBC; 137215), Gayther et al. (1998) found a 2095C-T transition in the CDH1 gene, resulting in an arg598-to-ter (R598X) substitution. The family was subsequently studied from the point of view of genetic screening, surgical management, and pathologic findings by Huntsman et al. (2001).
Gayther et al. (1998) found a 1-bp insertion in the CDH1 gene in the proband of a family with familial diffuse gastric cancer (DGLBC; 137215). Insertion of a G after nucleotide 1711 created a frameshift predicted to truncate the protein at codon 587. The family was subsequently studied from the point of view of genetic screening, surgical management, and pathologic findings by Huntsman et al. (2001).
In a family segregating diffuse gastric cancer (DGLBC; 137215), Guilford et al. (1999) identified a 1-bp insertion (1588insC) in exon 11 of the CDH1 gene. Chun et al. (2001) reported total gastrectomy as a prophylactic intervention in all 5 affected members of a family with diffuse gastric cancer and the 1588insC mutation.
In a Portuguese adult male with diffuse hereditary signet ring gastric carcinoma (DGLBC; 137215), Suriano et al. (2003) identified a 1901C-T transition in exon 12 of the CDH1 gene, which was predicted to result in an ala634-to-val (A634V) substitution. Cells transfected with this mutant cDNA exhibited decreased aggregation, increased invasiveness, and nonuniform migration in vitro compared to cells transfected with wildtype cDNA.
In a kindred of European origin with gastric cancer (DGLBC; 137215), Oliveira et al. (2002) identified a heterozygous 1018A-G transition in exon 8 of the CDH1 gene, resulting in a thr340-to-ala (T340A) substitution.
Suriano et al. (2003) observed that CHO cells expressing the T340A mutation failed to aggregate, showed invasive behavior, and migrated abnormally compared to wildtype cells in vitro.
In a Japanese family with diffuse gastric cancer (DGLBC; 137215), Yabuta et al. (2002) identified heterozygosity for a 2494G-A transition in exon 16 of the CDH1 gene, resulting in a val832-to-met (V832M) substitution.
Jonsson et al. (2004) genotyped 1,036 patients with sporadic familial (2 close relatives) or hereditary (3 or more close relatives) prostate cancer (176807) and 669 controls for the -160C/A promoter polymorphism (rs16260). The risk of hereditary prostate cancer was increased among CA carriers (odds ratio = 1.7) and AA carriers (odds ratio = 2.6) compared to controls; genotype frequencies did not differ between sporadic or familial cases and controls. Jonsson et al. (2004) concluded that CDH1 is a low-penetrant prostate cancer susceptibility gene that might explain a proportion of familial and particularly hereditary prostate cancer.
In an independent replication study population consisting of 612 patients with sporadic prostate cancer and 211 patients with at least 2 relatives with prostate cancer in a nuclear family (so-called 'FH+' cases) and 540 controls, Lindstrom et al. (2005) found strong evidence of an association between the -160C-A promoter polymorphism and risk of prostate cancer (p = 0.003) when comparing FH+ cases and controls. In the total study population, CA and AA carriers had an increased risk compared to CC carriers (odds ratio = 1.5 and 2.6, respectively). No significant difference in genotype frequency was observed between sporadic cases and controls.
Frebourg et al. (2006) described a Caucasian family in which 4 members had diffuse gastric cancer and cleft lip/palate (see 137215) and 2 other individuals had gastric cancer without clefting. Affected members of the family were shown to have a mutation of the intron 4 splicing donor site (531+2T-A). RT-PCR analysis of CDH1 from peripheral blood lymphocytes and sequence analysis of the amplified cDNA demonstrated that this mutation induced complex aberrant splicing including activation of an exonic cryptic donor splicing site.
Frebourg et al. (2006) found a splicing mutation affecting the last nucleotide of exon 8 of the CDH1 gene (1137G-A) in a man with hereditary diffuse gastric cancer (see 137215), his 2 daughters with gastric cancer, a daughter with cleft lip but no gastric cancer at age 25, and in a 16-year-old son who had congenital aplasia cutis of the scalp and partial acrania (see 107600) but no known gastric cancer.
In the germline of a woman who developed lobular breast cancer (DGLBC; 137215) at age 42 years, Masciari et al. (2007) identified a heterozygous 1-bp insertion (517insA) in the CDH1 gene, resulting in truncation of the extracellular portion of the protein. The breast cancer was negative for E-cadherin by immunostaining, and further analysis detected loss of heterozygosity of part of the gene. The patient's mother reportedly developed lobular breast cancer at age 28. No other breast or gastric cancers were reported in the family.
In 2 probands, one northern European and the other Canadian, with diffuse gastric cancer (DGLBC; 137215), who were both negative for germline CDH1 point mutations, Oliveira et al. (2009) identified the same 193.6-kb germline deletion involving the entire CDH3 gene (114021) and exons 1 and 2 of the CDH1 gene. The northern European proband, who also had lobular breast cancer, had 2 children and a grandchild diagnosed with diffuse gastric cancer at the age of 40, 37, and 28, respectively. Affected family members were not tested for the deletion. The Canadian proband developed diffuse gastric cancer at age 38 and again at age 43, and had 2 sisters who also developed diffuse gastric cancer at age 30 and 35, respectively, but they were not tested for the deletion. Haplotype analysis of microsatellite markers surround the CDH1 gene indicated that the 2 probands shared a 9-marker haplotype, demonstrating the existence of a common ancestor carrying the deletion.
In a European proband with diffuse gastric cancer (DGLBC; 137215) who was negative for germline CDH1 point mutations, Oliveira et al. (2009) identified an 828-bp deletion/3-bp insertion in the CDH1 gene. The deletion affected exon 16. The proband's mother had died of gastric cancer of unconfirmed histology as had 2 relatives, and 2 other relatives had died of diffuse gastric cancer and lobular breast cancer. The proband's 2 sisters were diagnosed with diffuse gastric cancer, and 1 was tested for the deletion and proved to be a carrier as had her 2 asymptomatic children.
In a mother and daughter with blepharocheilodontic syndrome (BCDS1; 119580), Ghoumid et al. (2017) identified heterozygosity for a splice site mutation (c.1320+1G-C, NM_004360.3) in intron 8 of the CDH1 gene, predicted to disrupt the canonical consensus donor motif and cause skipping of exon 9. RT-PCR of patient lymphocyte RNA confirmed exon 9 skipping, which was expected to induce removal of most of the EC3 domain and impair its adhesive function. Western blot analysis of transfected HEK293T cells revealed no detectable E-cadherin with constructs expressing the c.1320+1G-C mutation. Immunofluorescence staining of transfected HEK293T cells showed loss of cytoplasmic membrane staining and intracytoplasmic perinuclear E-cadherin accumulation with the mutant compared to wildtype.
In monozygotic twin sisters with blepharocheilodontic syndrome (BCDS1; 119580), Ghoumid et al. (2017) identified heterozygosity for a de novo splice site mutation (c.1320G-T, NM_004360.3) in intron 8 of the CDH1 gene, predicted to disrupt the canonical consensus donor motif and cause skipping of exon 9. Neither of her unaffected parents carried the mutation. Western blot analysis of transfected HEK293T cells revealed no detectable E-cadherin with constructs expressing the c.1320G-T mutation. Immunofluorescence staining of transfected HEK293T cells showed loss of cytoplasmic membrane staining, and intracytoplasmic perinuclear E-cadherin accumulation, with the mutant compared to wildtype.
In a female patient with blepharocheilodontic syndrome (BCDS1; 119580), Ghoumid et al. (2017) identified heterozygosity for a c.760G-T transversion (c.760G-T, NM_004360.3) in exon 6 of the CDH1 gene, resulting in an asp254-to-tyr (D254Y) substitution at a highly conserved residue within the calcium-binding pocket. The mutation was also present in her unaffected mother, suggesting incomplete penetrance. Western blot analysis of transfected HEK293T cells revealed no detectable E-cadherin with constructs expressing the D254Y mutation. Immunofluorescence staining of transfected HEK293T cells showed loss of cytoplasmic membrane staining and intracytoplasmic perinuclear E-cadherin accumulation with the mutant compared to wildtype.
In a Japanese girl with blepharocheilodontic syndrome (BCDS1; 119580), Nishi et al. (2016) identified heterozygosity for a de novo c.2028C-A transversion (c.2028C-A, NM_004360) in exon 13 of the CDH1 gene, resulting in an asp676-to-glu (D676E) substitution within an extracellular cadherin repeat. Neither of her unaffected parents carried the mutation.
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