Alternative titles; symbols
HGNC Approved Gene Symbol: CTNND1
Cytogenetic location: 11q12.1 Genomic coordinates (GRCh38): 11:57,761,802-57,819,540 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q12.1 | Blepharocheilodontic syndrome 2 | 617681 | Autosomal dominant | 3 |
Catenins were discovered as proteins that are linked ('catena' means 'chain' in Latin) to the cytoplasmic domain of transmembrane cadherin (see 601120) proteins. Delta-catenin, also called CAS, p120(cas), or p120(ctn), is a tyrosine kinase substrate implicated in ligand-induced receptor signaling through the EGF receptor (131550), the PDGF receptor (PDGFR; see 173490), and the CSF1 receptor (164770), as well as in cell transformation by SRC (190090). Delta-catenin is a major component of multiprotein cell-cell adhesion complexes containing E-cadherin (192090), alpha-catenin (116805), beta-catenin (116806), and gamma-catenin, also known as plakoglobin (173325) (summary by Keirsebilck et al., 1998).
Reynolds et al. (1992) isolated a mouse p120(ctn) cDNA. Like beta-catenin and plakoglobin, the predicted protein contains copies of a repeat originally identified in the Drosophila 'Armadillo' protein.
Keirsebilck et al. (1998) identified human p120(ctn) isoforms, which they designated 1 to 4, that arise by alternative use of start codons and additional isoforms that differ due to alternative splicing of 3 exons, which they named A, B, and C. The longest isoform was of type 1ABC and contained 968 amino acids. Isoform 1A contains 933 amino acids and is 97% identical to mouse p120(ctn). Human p120(ctn) contains up to 10 Armadillo repeats. Keirsebilck et al. (1998) used RT-PCR to demonstrate tissue-specific and cell line-specific expression of various isoforms.
Independently, Nagase et al. (1997) identified KIAA0384, a human p120(ctn) cDNA that encodes isoform 1AC, in a screen for brain cDNAs encoding proteins larger than 100 kD. RT-PCR detected expression in all tissues examined except skeletal muscle. Highest expression was detected in placenta, lung, liver, and kidney, followed by ovary and small intestine.
Keirsebilck et al. (1998) determined that the human p120(ctn) gene contains 21 exons, potentially encoding up to 32 protein isoforms as products of alternative splicing.
By fluorescence in situ hybridization, Reynolds et al. (1996) determined that the human gene, symbolized CTNND, is localized immediately adjacent to the centromere in band 11q11. By interspecific backcross analysis, they assigned the murine gene, symbolized Catns, to the middle of mouse chromosome 2. By analysis of radiation hybrids, Nagase et al. (1997) confirmed that the p120 gene maps to human chromosome 11. By fluorescence in situ hybridization and analysis of a somatic cell hybrid mapping panel, Bonne et al. (1998) mapped the CTNND1 gene to chromosome 11q11.
Dillon et al. (1998) reported that a complete loss of p120(ctn) expression was observed in approximately 10% of invasive ductal breast carcinomas investigated.
Wildenberg et al. (2006) found that depletion of p120-catenin in NIH3T3 mouse fibroblasts by small interfering RNA caused constitutive activation of Rho (RHOA; 165390), cell transformation, loss of contact inhibition, and growth in the absence of serum. Moreover, Pdgfr and integrin (see 135630) signaling pathways involved in remodeling the actin cytoskeleton were selectively impaired. Wildenberg et al. (2006) traced these effects to obligatory roles of p120-catenin and Arhgap5 (602680) in a pathway that connects Rac (RAC1; 602048) activation to Rho inhibition. They concluded that p120-catenin and ARHGAP5 use Rho GTPases to mediate crosstalk between a wide variety of receptors to coordinate cadherin function with other activities that direct cell adhesion, motility, and proliferation.
In 4 patients from 3 unrelated families with blepharocheilodontic syndrome (BCDS2; 617681), Ghoumid et al. (2017) identified heterozygosity for 3 different truncating mutations in the CTNND1 gene (601045.0001-601045.0003).
Using conditional targeting of p120(ctn) in mouse epidermis, Perez-Moreno et al. (2006) found that p120-null neonatal epidermis exhibited reduced intercellular adherens junction components, but no overt disruption in barrier function or intercellular adhesion. As the mice aged, they displayed epidermal hypoplasia and chronic inflammation, typified by hair degeneration and loss of body fat. Use of skin engraftments and antiinflammatory drugs showed that these features were not due to reductions in junctional cadherins and catenins, but rather to NF-kappa-B (see 164011) activation. Both in vivo and in vitro, p120-null epidermal cells activated NF-kappa-B, triggering a cascade of proinflammatory NF-kappa-B targets. NF-kappa-B activation in p120-null keratinocytes was accompanied by alterations in Rho GTPase activity that appeared to reside upstream from NF-kappa-B activation and downstream from p120 loss.
In a mother and son with blepharocheilodontic syndrome (BCDS2; 617681), Ghoumid et al. (2017) identified heterozygosity for a c.2098C-T transition (c.2098C-T, NM_001085458.1) in exon 14 of the CTNND1 gene, resulting in an arg700-to-ter (R700X) substitution that was predicted to affect isoforms 1, 2, and 3.
In a male patient with blepharocheilodontic syndrome (BCDS2; 617681), Ghoumid et al. (2017) identified heterozygosity for a de novo c.1093C-T transition (c.1093C-T, NM_001085458.1) in exon 7 of the CTNND1 gene, resulting in a gln365-to-ter (Q365X) substitution that was predicted to affect isoforms 1, 2 and 3. The mutation was not found in either of his unaffected parents.
In a male patient with blepharocheilodontic syndrome (BCDS2; 617681), Ghoumid et al. (2017) identified heterozygosity for a 1-bp deletion (c.606del, NM_001085458.1) in exon 6 of the CTNND1 gene, causing a frameshift predicted to result in a premature termination codon (Pro203LeufsTer25). The mutation was also present in his unaffected mother, suggesting incomplete penetrance.
Bonne, S., van Hengel, J., van Roy, F. Chromosomal mapping of human armadillo genes belonging to the p120(ctn)/plakophilin subfamily. Genomics 51: 452-454, 1998. [PubMed: 9721216] [Full Text: https://doi.org/10.1006/geno.1998.5398]
Dillon, D. A., D'Aquila, T., Reynolds, A. B., Fearon, E. R., Rimm, D. L. The expression of p120ctn protein in breast cancer is independent of alpha- and beta-catenin and E-cadherin. Am. J. Path. 152: 75-82, 1998. [PubMed: 9422525]
Ghoumid, J., Stichelbout, M., Jourdain, A.-S., Frenois, F., Lejeune-Dumoulin, S., Alex-Cordier, M.-P., Lebrun, M., Guerreschi, P., Duquennoy-Martinot, V., Vinchon, M., Ferri, J., Jung, M., Vicaire, S., Vanlerberghe, C., Escande, F., Petit, F., Manouvrier-Hanu, S. Blepharocheilodontic syndrome is a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1. Genet. Med. 19: 1013-1021, 2017. [PubMed: 28301459] [Full Text: https://doi.org/10.1038/gim.2017.11]
Keirsebilck, A., Bonne, S., Staes, K., van Hengel, J., Nollet, F., Reynolds, A., van Roy, F. Molecular cloning of the human p120(ctn) catenin gene (CTNND1): expression of multiple alternatively spliced isoforms. Genomics 50: 129-146, 1998. [PubMed: 9653641] [Full Text: https://doi.org/10.1006/geno.1998.5325]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Perez-Moreno, M., Davis, M. A., Wong, E., Pasolli, H. A., Reynolds, A. B., Fuchs, E. p120-catenin mediates inflammatory responses in the skin. Cell 124: 631-644, 2006. [PubMed: 16469707] [Full Text: https://doi.org/10.1016/j.cell.2005.11.043]
Reynolds, A. B., Herbert, L., Cleveland, J. L., Berg, S. T., Gaut, J. R. p120, a novel substrate of protein tyrosine kinase receptors and of p60v-src, is related to cadherin-binding factors beta-catenin, plakoglobin and armadillo. Oncogene 7: 2439-2445, 1992. [PubMed: 1334250]
Reynolds, A. B., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Shapiro, D. N., Wu, J., Daniel, J. M. The gene encoding p120(cas), a novel catenin, localizes on human chromosome 11q11 (CTNND) and mouse chromosome 2 (Catns). Genomics 31: 127-129, 1996. [PubMed: 8808291] [Full Text: https://doi.org/10.1006/geno.1996.0020]
Wildenberg, G. A., Dohn, M. R., Carnahan, R. H., Davis, M. A., Lobdell, N. A., Settleman, J., Reynolds, A. B. p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell 127: 1027-1039, 2006. [PubMed: 17129786] [Full Text: https://doi.org/10.1016/j.cell.2006.09.046]