Alternative titles; symbols
HGNC Approved Gene Symbol: CTNNA1
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38): 5:138,753,425-138,935,034 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.2 | Macular dystrophy, patterned, 2 | 608970 | Autosomal dominant | 3 |
E-cadherin is a transmembrane glycoprotein responsible for physical connection of epithelial cells through Ca(2+)-binding regions in its extracellular domain. E-cadherin-mediated cell-cell adhesion is effected by 3 cytoplasmic proteins known as catenins alpha, beta (see 116806), and gamma. These catenins are thought to work as connectors that anchor the E-cadherin to the cytoskeletal actin bundle through the cadherin cytoplasmic domain. Dysfunction of this adhesion complex causes dissociation of cancer cells from primary tumor nodules, thus possibly contributing to cancer invasion and metastasis. Herrenknecht et al. (1991) and Nagafuchi et al. (1991) isolated a murine cDNA encoding the 102-kD alpha-catenin (CAP102). Oda et al. (1993) cloned and sequenced human alpha-catenin. They found that it shows extensive homology with that of the mouse. Hirano et al. (1992) and Shimoyama et al. (1992) showed that a human lung cancer cell line, PC9, which expresses E-cadherin but only a small quantity of abnormal-sized alpha-catenin, grew initially as isolated cells and then regained its cell-cell adhesion potential when transfected with alpha-catenin. Oda et al. (1993) found 2 abnormal mRNA sequences of alpha-catenin in PC9; one was a 957-bp deletion resulting in a 319-amino acid deletion and another was a 761-bp deletion resulting in a frameshift. The deletions were thought to be responsible for the loss of alpha-catenin expression.
Furukawa et al. (1994) determined that the CTNNA1 gene encodes 906 amino acids. The 102-kD predicted protein is the same size as the murine homolog, and the amino acid sequences of the 2 proteins are 99.2% homologous. Analysis by reverse transcription-PCR demonstrated that the gene is expressed ubiquitously in normal tissues. The gene is expressed as a 3.4-kb transcript.
Furukawa et al. (1994) showed that the CTNNA1 gene consists of 16 coding exons and at least one 5-prime noncoding exon.
Crystal Structure
In adherens junctions, alpha-catenin links the cadherin/beta-catenin complex to the actin-based cytoskeleton. Alpha-catenin is a homodimer in solution, but forms a 1:1 heterodimer with beta-catenin. Pokutta and Weis (2000) determined the crystal structure of the alpha-catenin dimerization domain, residues 82 to 279. The crystal structure showed that alpha-catenin dimerizes through formation of a 4-helix bundle in which 2 antiparallel helices are contributed by each protomer. A slightly larger fragment, containing residues 57 to 264, bound to beta-catenin. The crystal structure of a chimera consisting of the alpha-catenin-binding region of beta-catenin linked to the N terminus of alpha-catenin residues 57 to 264 revealed the interaction between alpha- and beta-catenin and provided a basis for understanding adherens junction assembly.
By fluorescence in situ hybridization, Furukawa et al. (1994) mapped the CTNNA1 gene to 5q31.
McPherson et al. (1994) sequenced partial alpha-catenin cDNAs from a human prostate cDNA library and used these data to map the CTNNA1 gene by PCR analysis of a panel of somatic cell hybrids carrying various deletions. They concluded that the gene was located in the segment between mid 5q21 and distal 5q22. The discrepancy was resolved by Nollet et al. (1995), who characterized a catenin processed pseudogene (CTNNAP1) which shows 90% nucleotide sequence identity to the catenin functional gene (CTNNA1). The authors mapped the pseudogene to 5q22 and the functional gene to 5q31 by fluorescence in situ hybridization. Guenet et al. (1995) mapped the corresponding mouse gene (symbolized Catna1) to chromosome 18 by analysis of the segregation pattern of informative DNA polymorphisms among the progeny of 2 interspecific backcrosses.
Vasioukhin et al. (2001) examined the consequences of alpha-catenin protein ablation in otherwise normal newborn mice. When surface epithelium alpha-catenin was ablated, hair follicle development was blocked and epidermal morphogenesis was dramatically affected, with defects in adherens junction formation, intercellular adhesion, and epithelial polarity. Differentiation occurred, but epidermis displayed hyperproliferation, suprabasal mitoses, and multinucleated cells. In vitro, alpha-catenin null keratinocytes were poorly contact inhibited and grew rapidly. These differences were not dependent upon intercellular adhesion and were in marked contrast to keratinocytes conditionally null for another essential intercellular adhesion protein, desmoplakin (DSP; 125647). Knockout keratinocytes exhibited sustained activation of the Ras-MAPK cascade due to aberrations in growth factor responses. The authors concluded that features of precancerous lesions often attributed to defects in cell cycle regulatory genes can be generated by compromising the function of alpha-catenin.
Van Aken et al. (2002) studied the cadherin-catenin complex in retinoblastoma and normal retina tissues. In both cases, they found that N-cadherin (114020) was associated with alpha- and beta-catenin but not with E- or P-cadherin. Moreover, retinoblastoma cells, in contrast with normal retina, expressed an N-cadherin/catenin complex that was irregularly distributed and weakly linked to the cytoskeleton. In retinoblastoma, this complex acted as an invasion promoter.
Patterned Macular Dystrophy 2
In affected individuals from 3 unrelated families with patterned macular dystrophy-2 (MDPT2; 608970), Saksens et al. (2016) identified heterozygosity for missense mutations in the CTNNA1 gene (116805.0001-116805.0003) that segregated with disease and were not found in controls or the Exome Variant Server database.
Associations Pending Confirmation
Interstitial deletion of all or part of chromosome 5q is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Using primitive leukemia-initiating cells from individuals with MDS or AML, with or without a chromosome 5q deletion, Liu et al. (2007) analyzed the expression of 12 genes within the 5q31 common deleted region and found that CTNNA1 was expressed at a much lower level in cells from individuals with a 5q deletion than in cells from those without a 5q deletion or in normal hematopoietic cells. Analysis of HL-60 myeloid leukemia cells with deletion of the 5q31 region showed that the CTNNA1 promoter of the retained allele was suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Liu et al. (2007) concluded that loss of the CTNNA1 tumor suppressor gene in hematopoietic stem cells may provide a growth advantage that contributes to human MDS/AML with 5q deletion.
Ding et al. (2010) described the genomic analyses of 4 DNA samples from an African American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis, and a xenograft derived from the primary tumor. The metastasis contained 2 de novo mutations and a large deletion not present in the primary tumor, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumor mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions encompassing CTNNA1 were present in all 3 tumor samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumor indicated that secondary tumors may arise from a minority of cells with the primary tumor.
Lien et al. (2006) found that neural progenitors express alpha-E catenin while differentiated neurons express alpha-N catenin (114025). To study the role of alpha-E catenin in the central nervous system (CNS), Lien et al. (2006) created CNS-specific deletion of alpha-E catenin. Heterozygotes were similar to wildtype littermates. At embryonic day 12.5 alpha-E catenin-null mice were indistinguishable from their littermates, but by embryonic day 13.5 mutant brains displayed a 40% increase in total cell numbers. At birth, these pups were born with small bodies and enlarged heads; after birth the heads of these animals continued to grow but their bodies were developmentally retarded. Pups failed to thrive and died between 2 and 3 weeks of age. Histologic analysis of alpha-E catenin-null brains revealed severe dysplasia and hyperplasia. The ventricular zone cells were dispersed throughout the developing brains, forming invasive tumor-like masses that displayed widespread pseudopalisading and the formation of rosettes similar to Homer-Wright rosettes in human medulloblastoma, neuroblastoma, retinoblastoma, pineoblastoma, neurocytoma, and pineocytoma tumors. Alpha-E catenin-null embryos had a prominent increase in the thickness and size of the cerebral cortex. There was massive expansion of dysplastic cortical progenitor cells, causing a posterior and ventral shift in localization of the lateral ventricle. Lien et al. (2006) found that the hyperplasia in alpha-E catenin-null brains was the combined outcome of the shortening of the cell cycle and decreased apoptosis in neural progenitor cells. Using a microarray approach, Lien et al. (2006) determined that only 5 transcripts were upregulated and 3 downregulated in alpha-E catenin-null brains. The 2 most upregulated cDNAs, Fgf15 (see 603891) and Gli1 (165220), are transcriptional targets of the hedgehog (see 600725) pathway. Quantitative RT-PCR showed significant upregulation of Gli1, Fgf15, and Smoothened (601500). Lien et al. (2006) proposed that alpha-E catenin connects cell density-dependent adherens junctions with the developmental hedgehog pathway and that this connection may provide a negative feedback loop controlling the size of developing cerebral cortex.
Shibata et al. (2007) generated several familial adenomatous polyposis (FAP; 175100) mouse lines heterozygous for a ser580-to-asp (S580D) truncation mutation in the Apc gene (611731) and found that 1 line (line 19) showed reduced incidence of intestinal adenomas (less than 5% compared with other lines). They identified a deletion in the Ctnna1 gene as the cause of tumor suppression in line-19 Apc S580D/+ mice and found that suppression only occurred when the Ctnna1 deletion was in cis configuration with the Apc S580D mutation. In all adenomas generated in line-19 Apc S580D/+ mice, somatic recombination between Apc and Ctnna1 retained the wildtype Ctnna1 allele. Shibata et al. (2007) concluded that simultaneous inactivation of Ctnna1 and Apc during tumor initiation suppressed adenoma formation in line-19 Apc S580D/+ mice, suggesting that CTNNA1 plays an essential role in initiation of intestinal adenomas. They noted that evidence from human colon tumors with invasive or metastatic potential had established a tumor-suppressive role for CTNNA1 in late-stage tumorigenesis. Thus, Shibata et al. (2007) suggested that CTNNA1 has dual roles in intestinal tumorigenesis: a supporting role in tumor initiation and a suppressive role in tumor progression.
Li et al. (2012) observed progressive dilated cardiomyopathy approximately 8 months after induction of Ctnna1 deletion in mice. Increased expression of Ctnna3 (607667) at 3 months postinduction suggested that Ctnna3 may compensate, at least in part, for loss of Ctnna1 in mouse heart.
Saksens et al. (2016) identified a Ctnna1 missense mutation (L436P) in a chemically induced mouse mutant, tvrm5, and observed changes in the retinal pigment epithelium (RPE) parallel to those of patients with butterfly-shaped pigment dystrophy, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphologic studies in tvrm5 mice demonstrated increased cell shedding and the presence of large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis.
In affected members of a large Dutch family with patterned macular dystrophy-2 (MDPT2; 608970), originally described by Deutman et al. (1970), Saksens et al. (2016) identified heterozygosity for a c.953T-C transition (c.953T-C, NM_001903) in the CTNNA1 gene, resulting in a leu318-to-ser (L318S) substitution at a residue conserved among vertebrates. The mutation segregated with disease in the family and was not found in 162 ancestry-matched controls or in the Exome Variant Server database.
In a Dutch mother and son with patterned macular dystrophy-2 (MDPT2; 608970), Saksens et al. (2016) identified heterozygosity for a c.1293T-G transversion (c.1293T-G, NM_001903) in exon 9 of the CTNNA1 gene, resulting in an ile431-to-met (I431M) substitution at a residue conserved among vertebrates. The mutation was not found in 162 ancestry-matched controls or in the Exome Variant Server database.
In a Belgian mother and daughter with patterned macular dystrophy-2 (MDPT2; 608970), Saksens et al. (2016) identified heterozygosity for a c.919G-A transition (c.919G-A, NM_001903) in exon 7 of the CTNNA1 gene, resulting in a glu307-to-lys (E307K) substitution at a residue conserved among vertebrates. The mutation was not found in 162 ancestry-matched controls or in the Exome Variant Server database.
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