Alternative titles; symbols
HGNC Approved Gene Symbol: AXIN2
Cytogenetic location: 17q24.1 Genomic coordinates (GRCh38): 17:65,528,563-65,561,648 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q24.1 | Colorectal cancer, somatic | 114500 | 3 | |
| Oligodontia-colorectal cancer syndrome | 608615 | Autosomal dominant | 3 |
The Axin (603816)-related protein conductin, or axil, plays an important role in the regulation of the stability of beta-catenin (116806) in the Wnt signaling pathway. In mouse, conductin organizes a multiprotein complex of APC (611731), beta-catenin, glycogen synthase kinase-3-beta (GSK3B; 605004), and conductin, which leads to the degradation of beta-catenin. By RT-PCR with degenerate primers based on the rat axil cDNA sequence, Mai et al. (1999) isolated a human fetal brain cDNA encoding AXIN2, the human homolog of mouse conductin/rat axil. The predicted 843-amino acid AXIN2 protein is 89% identical to rat axil. Like axil, AXIN2 contains RGS-signaling (see 602517), GSK-binding, beta-catenin-binding, and Dsh (Drosophila dishevelled; see 601365) domains. By Northern blot analysis, Dong et al. (2001) detected ubiquitous expression of a 3.0-kb AXIN2 transcript, with highest levels in thymus, prostate, testis, ovary, and small intestine, lower levels in colon, and barely detectable levels in blood leukocytes.
Dong et al. (2001) determined that the AXIN2 gene contains 10 exons and spans more than 25 kb of genomic DNA.
Using mouse lineage tracing and quantitative clonal analyses, Lim et al. (2013) showed that the Wnt target gene Axin2 marks interfollicular epidermal stem cells. These Axin2-expressing cells constitute the majority of the basal epidermal layer, compete neutrally, and require Wnt/beta-catenin (116806) signaling to proliferate. The same cells contribute robustly to wound healing, with no requirement for a quiescent stem cell subpopulation. By means of double-labeling RNA in situ hybridization in mice, Lim et al. (2013) showed that the Axin2-expressing cells themselves produce Wnt signals as well as long-range secreted Wnt inhibitors, suggesting an autocrine mechanism of stem cell self-renewal.
Using lineage tracing in mice, Wang et al. (2015) found that Axin2 identifies a population of proliferating and self-renewing cells adjacent to the central vein in the liver lobule. These pericentral cells express the early liver progenitor marker Tbx3 (601621) and are diploid, and thereby differ from mature hepatocytes, which are mostly polyploid. The descendants of pericentral cells differentiate into Tbx3-negative, polyploid hepatocytes, and can replace all hepatocytes along the liver lobule during homeostatic renewal. Adjacent central vein endothelial cells provide Wnt signals that maintain the pericentral cells, thereby constituting the niche. Wang et al. (2015) concluded that they identified a cell population in the liver that subserves homeostatic hepatocyte renewal, characterizes its anatomic niche, and identifies molecular signals that regulate its activity.
Sigal et al. (2017) found that antral Wnt signaling, marked by the classic Wnt target gene Axin2, is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5 (606667)+ cells, as well as adjacent, highly proliferative Lgr5- cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5+ population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin-3 (RSPO3; 610574) produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2+/Lgr5- but not Lgr5+ cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2+ cell pool to cause hyperproliferation and gland hyperplasia.
By analysis of radiation hybrids, Mai et al. (1999) mapped the AXIN2 gene to 17q23-q24, a region that shows frequent loss of heterozygosity in breast cancer, neuroblastoma, and other tumors. By FISH, Dong et al. (2001) mapped the AXIN2 gene to 17q24 and showed that it exists in single copy.
Oligodontia-Colorectal Cancer Syndrome
In a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal cancer (608615) segregated with dominant inheritance, Lammi et al. (2004) identified an arg656-to-ter mutation in the AXIN2 gene (R656X; 604025.0003). At least 8 permanent teeth were missing in 11 members of the family, 2 of whom developed only 3 permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in 8 of the patients with oligodontia. In addition, Lammi et al. (2004) identified a de novo frameshift mutation in the AXIN2 gene in an unrelated young patient with severe tooth agenesis. Both mutations were expected to activate Wnt signaling. The results provided the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggested that an intricate control of Wnt signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. The findings also identified AXIN2 as a gene that is responsible for hereditary colorectal cancer and suggested that tooth agenesis may be an indicator of cancer susceptibility.
In 2 cohorts of patients with tooth agenesis, including 116 from Brazil and 51 from Turkey, Callahan et al. (2009) analyzed 3 SNPs in the AXIN2 gene (rs7591, rs11867417, and rs2240308) and found a significant association between tooth agenesis and variation in AXIN2 in cases with at least 1 missing incisor (combined p for 'T-C-A' haplotype = 0.02). Callahan et al. (2009) stated that their results supported a role for AXIN2 in tooth agenesis.
In a 3-generation family segregating autosomal dominant oligodontia variably associated with colon or gastric polyps, early-onset colorectal and/or breast cancer, and sparse hair and eyebrows, Marvin et al. (2011) identified a heterozygous nonsense mutation in the AXIN2 gene (W663X; 604025.0004).
Colorectal Cancer
Colorectal cancer (CRC; 114500) with defective DNA mismatch repair (MMR) is associated with alterations in one of several DNA MMR genes, e.g., MLH1 (120436) and MSH2 (609309). Liu et al. (2000) showed that AXIN2 was mutated in 11 of 45 CRC tumors with defective MMR (see, e.g., 604025.0001-604025.0002). They showed that the mutations stabilize beta-catenin (116806) and activate beta-catenin/T-cell factor signaling. Preliminary data suggested that AXIN2 is overexpressed in CRC. Mutant AXIN2 is more stable in colon cancer cells than is the wildtype protein. A related protein, AXIN1 (603816), is mutant in cases of hepatocellular carcinoma.
In colorectal cancers (114500) from 6 patients, Liu et al. (2000) found a frameshift mutation in the AXIN2 gene: 2084insG, predicting a glu706-to-ter (E706X) nonsense mutation.
In the colorectal cancers (114500) of 3 unrelated patients, Liu et al. (2000) found a 2083delG frameshift mutation in the AXIN2 gene, predicting a leu688-to-ter (L688X) stop codon.
In affected members of a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal cancer (ODCRCS; 608615) segregated with dominant inheritance, Lammi et al. (2004) identified a 1966C-T transition in exon 7 of the AXIN2 gene, resulting in an arg656-to-ter (R656X) mutation. At least 8 permanent teeth were missing in 11 members of the family, 2 of whom developed only 3 permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in 8 of the patients with oligodontia.
In 4 affected members of a 3-generation family segregating autosomal dominant oligodontia variably associated with colon or gastric polyps, early-onset colorectal and/or breast cancer, and sparse hair and eyebrows (ODCRCS; 608615), Marvin et al. (2011) identified heterozygosity for a 1989G-A transition in the AXIN2 gene, resulting in a trp663-to-ter (W663X) substitution. The mutation was not found in 2 unaffected family members. Expression of the mutant construct in HEK293 cells produced an approximately 80-kD protein representing a truncated AXIN2 product missing the last 3 exons.
Callahan, N., Modesto, A., Meira, R., Seymen, F., Patir, A., Vieira, A. R. Axis inhibition protein 2 (AXIN2) polymorphisms and tooth agenesis. Arch. Oral Biol. 54: 45-49, 2009. [PubMed: 18790474] [Full Text: https://doi.org/10.1016/j.archoralbio.2008.08.002]
Dong, X., Seelan, R. S., Qian, C., Mai, M., Liu, W. Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Cytogenet. Cell Genet. 93: 26-28, 2001. [PubMed: 11474173] [Full Text: https://doi.org/10.1159/000056942]
Lammi, L., Arte, S., Somer, M., Jarvinen, H., Lahermo, P., Thesleff, I., Pirinen, S., Nieminen, P. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am. J. Hum. Genet. 74: 1043-1050, 2004. [PubMed: 15042511] [Full Text: https://doi.org/10.1086/386293]
Lim, X., Tan, S. H., Koh, W. L. C., Chau, R. M. W., Yan, K. S., Kuo, C. J., van Amerongen, R., Klein, A. M., Nusse, R. Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling. Science 342: 1226-1230, 2013. [PubMed: 24311688] [Full Text: https://doi.org/10.1126/science.1239730]
Liu, W., Dong, X., Mai, M., Seelan, R. S., Taniguchi, K., Krishnadath, K. K., Halling, K. C., Cunningham, J. M., Boardman, L. A., Qian, C., Christensen, E., Schmidt, S. J., Roches, P. C., Smith, D. I., Thibodeau, S. N. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nature Genet. 26: 146-147, 2000. Note: Erratum: Nature Genet. 26: 501 only, 2000. [PubMed: 11017067] [Full Text: https://doi.org/10.1038/79859]
Mai, M., Qian, C., Yokomizo, A., Smith, D. I., Liu, W. Cloning of the human homolog of conductin (AXIN2), a gene mapping to chromosome 17q23-q24. Genomics 55: 341-344, 1999. [PubMed: 10049590] [Full Text: https://doi.org/10.1006/geno.1998.5650]
Marvin, M. L., Mazzoni, S. M., Herron, C. M., Edwards, S., Gruber, S. B., Petty, E. M. AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome. Am. J. Med. Genet. 155A: 898-902, 2011. [PubMed: 21416598] [Full Text: https://doi.org/10.1002/ajmg.a.33927]
Sigal, M., Logan, C. Y., Kapalczynska, M., Mollenkopf, H.-J., Berger, H., Wiedenmann, B., Nusse, R., Amieva, M. R., Meyer, T. F. Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. Nature 548: 451-455, 2017. [PubMed: 28813421] [Full Text: https://doi.org/10.1038/nature23642]
Wang, B., Zhao, L., Fish, M., Logan, C. Y., Nusse, R. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524: 180-185, 2015. [PubMed: 26245375] [Full Text: https://doi.org/10.1038/nature14863]