Alternative titles; symbols
HGNC Approved Gene Symbol: CTNNA3
Cytogenetic location: 10q21.3 Genomic coordinates (GRCh38) : 10:65,912,523-67,763,594 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q21.3 | Arrhythmogenic right ventricular dysplasia 13 | 615616 | Autosomal dominant | 3 |
CTNNA3 is a cell adhesion molecule. In intercalated discs of the heart, CTNNA3 is a component of a unique hybrid adhering junction, or area composita, that contains proteins associated with both desmosomes and adherens junctions (Li et al., 2012).
By searching an EST database for sequences similar to alpha-E-catenin (CTNNA1; 116805), followed by 5-prime RACE of testis mRNA, Janssens et al. (2001) cloned full-length CTNNA3. The deduced 895-amino acid protein has a calculated molecular mass of 100 kD and contains 3 vinculin (193065) homology domains. It shares about 57% amino acid identity with other alpha-catenins. PCR detected CTNNA3 expression mainly in heart and testis. Lower amounts were also detected in brain, kidney, liver, fetal liver, and skeletal muscle. RT-PCR of mouse tissues showed a similar, but not identical, pattern of expression. Immunolocalization of CTNNA3 in cryosections of human heart revealed CTNNA3 at intercalated discs of cardiomyocytes, where it colocalized with alpha-E-catenin. In testis, CTNNA3 localized to desmin (125660)-expressing peritubular myoid cells, but it did not colocalize with alpha-E-catenin.
Janssens et al. (2001) found that transfection of CTNNA3 in alpha-catenin-deficient colon carcinoma cells recruited E-cadherin (CDH1; 192090) and beta-catenin (CTNBB1; 116806) to cell-cell contacts and restored functional cadherin-mediated cell-cell adhesion. Moreover, compaction of transfected cells was at least as prominent as in cells expressing endogenous alpha-E-catenin. Janssens et al. (2001) proposed that CTNNA3 is necessary for the formation of stretch-resistant cell-cell adhesion complexes in muscle cells.
Janssens et al. (2003) determined the structure of the mouse and human CTNNA3 genes. The human CTNNA3 gene contains 18 exons and spans about 1,776 kb. The exon-exon boundaries of human CTNNA3 and CTNNA2 (114025) and of mouse Ctnna3 are completely conserved. The boundaries also overlap extensively with those of the CTNNA1 and CTNNAL1 (604785) genes. The authors concluded that the alpha-catenin genes evolved from the same ancestral gene. The introns of human and mouse CTNNA3 are, however, remarkably large (often more than 100 kb) compared with the introns of other CTNNA genes.
Janssens et al. (2003) mapped the CTNNA3 gene to chromosome 10q21 by fluorescence in situ hybridization and PCR-based hybrid mapping.
Arrhythmogenic Right Ventricular Dysplasia 13
In 76 Italian probands with arrhythmogenic right ventricular dysplasia (ARVD13; 615616) who were negative for mutation in 5 known ARVD-associated genes, van Hengel et al. (2013) analyzed the candidate gene CTNNA3 and identified different heterozygous mutations in 2 of the probands, a missense mutation (V94D; 607667.0001) and an in-frame 3-bp deletion (607667.0002). Neither mutation was found in 250 ethnically matched controls or in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
Possible Association with Alzheimer Disease
For a discussion of a possible association between variation in the CTNNA3 gene and susceptibility to Alzheimer disease, see AD6 (605526).
Possible Association with Preeclampsia 4
By using complementary in vitro and ex vivo approaches, van Dijk et al. (2010) showed that the STOX1 preeclampsia (PEE4; 609404) risk allele Y153H (609397.0001) negatively regulated trophoblast invasion by upregulation of alpha-T-catenin. This was effectuated at the crucial epithelial-mesenchymal transition from proliferative into invasive extravillous trophoblast. The STOX1-CTNNA3 interaction was direct and included the Akt (164730)-mediated phosphorylated control of nucleocytoplasmic shuttling and ubiquitin-mediated degradation similar to that of FOX multigene family members (see, e.g., FOXO3A, 602681). The authors concluded that Y153H directly limits first-trimester extravillous trophoblast invasion, the earliest hallmark of preeclampsia.
Exclusion Studies
Because of the map location of the CTNNA3 gene and its high expression in heart tissues, Janssens et al. (2003) considered it as a candidate for the form of dilated cardiomyopathy linked to 10q21-q23 (CMD1C; 601493). Mutation screening of all 18 exons of the CTNNA3 gene in 1 affected family revealed no mutations.
Li et al. (2012) found that Ctnna3 -/- mice were viable and fertile and showed no obvious macroscopic abnormality. However, Ctnna3 -/- mice exhibited progressive cardiomyopathy and increased incidence of ventricular arrhythmias, including fatal arrhythmias, after acute ischemia. Intercalated discs of Ctnna3 -/- hearts appeared largely normal by transmission electron microscopy, but plakophilin-2 (PKP2; 602861), which is implicated in the formation, organization, and stability of composita junctions, was lost from Ctnna3 -/- intercalated discs. Pkp2 localization at desmosomes appeared normal. Cultured Ctnna3 -/- cardiomyocytes showed reduced colocalization of the gap junction protein Cx43 (GJA1; 121014) with Pkp2 at intercalated discs.
In an Italian man with arrhythmogenic right ventricular dysplasia (ARVD13; 615616), van Hengel et al. (2013) identified heterozygosity for a de novo c.281T-A transversion in exon 3 of the CTNNA3 gene, resulting in a val94-to-asp (V94D) substitution at a highly conserved residue in the beta-catenin binding and homodimerization complex in the VH1 domain. The mutation was not found in 250 ethnically matched controls or in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Transfection studies in neonatal rat cardiomyocytes and HL-1 mouse cardiomyocytes showed the V94D mutant predominantly and consistently localized in the cytoplasm, in contrast to wildtype CTNNA3 which was detected at cell-cell contacts and colocalized with endogenous beta-catenin (CTNNB1; 116806). In MCF7/AZ cells, beta-catenin colocalized with wildtype CTNNA3 but not the V94D mutant, and yeast 2-hybrid analysis showed that V94D did not interact with beta-catenin or plakoglobin (JUP; 173325).
In an Italian female proband with arrhythmogenic right ventricular dysplasia (ARVD13; 615616), van Hengel et al. (2013) identified heterozygosity for an in-frame 3-bp deletion (c.2293_2295delTTG) in exon 17 of the CTNNA3 gene, resulting in deletion of leu765 (Leu765del) at a highly conserved residue in the F-actin binding domain of VH3. The mutation was also present in heterozygosity in the proband's asymptomatic father and paternal aunt, who had mild right ventricular dilation on echocardiography and increased trabeculations in the right ventricular apex on MRI, respectively, as well as in the aunt's asymptomatic son. The mutation was not found in 250 ethnically matched controls or in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Transfection studies in neonatal rat cardiomyocytes and HL-1 mouse cardiomyocytes demonstrated that the Leu765del mutant, like wildtype CTNNA3, was present at cell-cell contacts and colocalized with endogenous beta-catenin (CTNNB1; 116806). However, the Leu765del mutant showed a stronger dimerization potential in yeast and formed aggresomes in HEK293T transfectants.
Janssens, B., Goossens, S., Staes, K., Gilbert, B., van Hengel, J., Colpaert, C., Bruyneel, E., Mareel, M., van Roy, F. Alpha-T-catenin: a novel tissue-specific beta-catenin-binding protein mediating strong cell-cell adhesion. J. Cell Sci. 114: 3177-3188, 2001. [PubMed: 11590244] [Full Text: https://doi.org/10.1242/jcs.114.17.3177]
Janssens, B., Mohapatra, B., Vatta, M., Goossens, S., Vanpoucke, G., Kools, P., Montoye, T., van Hengel, J., Bowles, N. E., van Roy, F., Towbin, J. A. Assessment of the CTNNA3 gene encoding human alpha-T-catenin regarding its involvement in dilated cardiomyopathy. Hum. Genet. 112: 227-236, 2003. [PubMed: 12596047] [Full Text: https://doi.org/10.1007/s00439-002-0857-5]
Li, J., Goossens, S., van Hengel, J., Gao, E., Cheng, L., Tyberghein, K., Shang, X., De Rycke, R., van Roy, F., Radice, G. L. Loss of alpha-T-catenin alters the hybrid adhering junctions in the heart and leads to dilated cardiomyopathy and ventricular arrhythmia following acute ischemia. J. Cell Sci. 125: 1058-1067, 2012. [PubMed: 22421363] [Full Text: https://doi.org/10.1242/jcs.098640]
van Dijk, M., van Bezu, J., van Abel, D., Dunk, C., Blankenstein, M. A., Oudejans, C. B. M., Lye, S. J. The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation. Hum. Molec. Genet. 19: 2658-2667, 2010. [PubMed: 20400461] [Full Text: https://doi.org/10.1093/hmg/ddq152]
van Hengel, J., Calore, M., Bauce, B., Dazzo, E., Mazzotti, E., De Bortoli, M., Lorenzon, A., Li Mura, I. E. A., Beffagna, G., Rigato, I., Vleeschouwers, M., Tyberghein, K., and 10 others. Mutations in the area composita protein alpha-T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. Europ. Heart J. 34: 201-210, 2013. [PubMed: 23136403] [Full Text: https://doi.org/10.1093/eurheartj/ehs373]