Alternative titles; symbols
HGNC Approved Gene Symbol: CTNNB1
Cytogenetic location: 3p22.1 Genomic coordinates (GRCh38): 3:41,199,505-41,240,443 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.1 | Colorectal cancer, somatic | 114500 | 3 | |
| Exudative vitreoretinopathy 7 | 617572 | Autosomal dominant | 3 | |
| Hepatocellular carcinoma, somatic | 114550 | 3 | ||
| Medulloblastoma, somatic | 155255 | 3 | ||
| Neurodevelopmental disorder with spastic diplegia and visual defects | 615075 | Autosomal dominant | 3 | |
| Ovarian cancer, somatic | 167000 | 3 | ||
| Pilomatricoma, somatic | 132600 | 3 |
Beta-catenin is an adherens junction protein. Adherens junctions (AJs; also called the zonula adherens) are critical for the establishment and maintenance of epithelial layers, such as those lining organ surfaces. AJs mediate adhesion between cells, communicate a signal that neighboring cells are present, and anchor the actin cytoskeleton. In serving these roles, AJs regulate normal cell growth and behavior. At several stages of embryogenesis, wound healing, and tumor cell metastasis, cells form and leave epithelia. This process, which involves the disruption and reestablishment of epithelial cell-cell contacts, may be regulated by the disassembly and assembly of AJs. AJs may also function in the transmission of the 'contact inhibition' signal, which instructs cells to stop dividing once an epithelial sheet is complete (summary by Peifer, 1993).
As reviewed by Peifer (1993), the AJ is a multiprotein complex assembled around calcium-regulated cell adhesion molecules called cadherins (e.g., 114020 and 114021). Cadherins are transmembrane proteins: the extracellular domain mediates homotypic adhesion with cadherins on neighboring cells, and the intracellular domain interacts with cytoplasmic proteins that transmit the adhesion signal and anchor the AJ to the actin cytoskeleton. These cytoplasmic proteins include the alpha- (116805), beta-, and gamma-catenins. The beta-catenin gene, which was cloned by McCrea et al. (1991), shows no similarity in sequence to the genes for the alpha-catenins. The beta-catenin protein shares 70% amino acid identity with both plakoglobin (173325), which is found in desmosomes (another type of intracellular junction), and the product of the Drosophila segment polarity gene 'armadillo.' Armadillo is part of a multiprotein AJ complex in Drosophila that also includes some homologs of alpha-catenin and cadherin, and genetic studies indicate that it is required for cell adhesion and cytoskeletal integrity. The armadillo gene was originally identified as one of a group of segment polarity genes that regulate pattern formation of the Drosophila embryonic cuticle.
Nollet et al. (1996) showed that the CTNNB1 gene has 16 exons and spans 23.2 kb. Alternative splicing within exon 16 produced a splice variant that is 159-bp shorter in the 3-prime untranslated region. The promoter region was shown to be GC-rich and to contain a TATA box. The authors demonstrated promoter activity in mouse epithelial cells for the 5-prime flanking region when it was linked to the reporter gene alkaline phosphatase.
By FISH, Kraus et al. (1994) mapped the CTNNB1 gene to 3p21, a region frequently affected by somatic alterations in a variety of tumors. Using PCR primers for the genomic amplification of beta-catenin sequences on the basis of homology to exon 4 of the Drosophila armadillo gene, they analyzed a panel of somatic cell hybrids to confirm the localization of the gene to human chromosome 3. Exclusion mapping of 3 hybrids carrying defined fragments of 3p allowed them to determine that the CTNNB1 locus is close to marker D3S2. Guenet et al. (1995) mapped the homologous gene, symbolized Catnb by them, to mouse chromosome 9 by analysis of interspecific backcrosses. Bailey et al. (1995) used FISH and PCR analysis of somatic cell hybrid DNAs to show that the CTNNB1 gene is located in the 3p22-p21 region. By FISH, van Hengel et al. (1995) assigned CTNNB1 to 3p22-p21.3. Trent et al. (1995) likewise localized the CTNNB1 gene to 3p22 by FISH. They stated that because APC-binding proteins (like beta-catenin) represent a 'downstream' modulator of APC activity, the chromosomal locus of such a protein might be expected to be a site involved in chromosome rearrangements in malignancy.
Work by Korinek et al. (1997) and by Morin et al. (1997) established that the APC gene (611731), which is mutant in adenomatous polyposis of the colon, is a negative regulator of beta-catenin signaling. The APC protein normally binds to beta-catenin, which interacts with Tcf and Lef transcription factors. Korinek et al. (1997) cloned a gene, which they called hTcf-4, that is a Tcf family member expressed in colonic epithelium. The protein product (Tcf4) transactivates transcription only when associated with beta-catenin. Nuclei of APC -/- colon carcinoma cells were found to contain a stable beta-catenin/Tcf4 complex that was constitutively active, as measured by transcription of a Tcf reporter gene. Reintroduction of APC removed beta-catenin from Tcf4 and abrogated the transcriptional activation. Korinek et al. (1997) concluded that constitutive transcription of Tcf target genes, caused by loss of APC function, may be a crucial event in the early transformation of colonic epithelium. Morin et al. (1997) likewise found that the protein products of mutant APC genes present in colorectal tumors were defective in downregulating transcriptional activation mediated by beta-catenin and T-cell transcription factor-4 (TCF4), now known as transcription factor-7-like-2 (TCF7L2; 602228). Furthermore, colorectal tumors with intact APC genes were found to contain activating mutations of beta-catenin that altered functionally significant phosphorylation sites. These results indicated that regulation of beta-catenin is critical to the tumor suppressive effect of APC and that this regulation can be circumvented by mutations in either APC or beta-catenin.
Roose et al. (1999) demonstrated in mice that one of the targets of the beta-catenin/TCF7L2 interactions in epithelial cells is TCF7 (189908). Roose et al. (1999) suggested that TCF7 may act as a feedback repressor of beta-catenin/TCF7L2 target genes, and thus may cooperate with APC to suppress malignant transformation of epithelial cells.
Rodova et al. (2002) presented evidence for beta-catenin-induced expression of PKD1 (601313). They analyzed the promoter region of PKD1 and identified numerous transactivating factors, including 4 TCF-binding elements (TBEs). Beta-catenin induced a reporter construct containing TBE1 6-fold when cotransfected into HEK293T cells, which express TCF4 (TCF7L2). Dominant-negative TCF4 or deletion of the TBE1 sequence inhibited the induction. Gel shift assays confirmed that TCF4 and beta-catenin could complex with the TBE1 site, and HeLa cells stably transfected with beta-catenin responded with elevated levels of endogenous PKD1 mRNA. Rodova et al. (2002) concluded that the PKD1 gene is a target of the beta-catenin/TCF pathway.
Van de Wetering et al. (2002) showed that disruption of beta-catenin/TCF4 activity in colorectal cancer cells induced a rapid G1 arrest and blocked a genetic program that was physiologically active in the proliferative compartment of colon crypts. Coincidentally, an intestinal differentiation program was induced. The TCF4 target gene MYC (190080) played a central role in this switch by direct repression of the CDKN1A (116899) promoter. Following disruption of beta-catenin/TCF4 activity, the decreased expression of MYC released CDKN1A transcription, which in turn mediated G1 arrest and differentiation. The authors concluded that the beta-catenin/TCF4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells.
Glucuronic acid epimerase (GLCE; 612134) is responsible for epimerization of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) of the cell surface polysaccharide heparan sulfate (HS), endowing the nascent HS polysaccharide chain with the ability to bind growth factors and cytokines. Using stepwise deletion and site-directed mutagenesis, Ghiselli and Agrawal (2005) identified 2 cis-acting binding elements for the beta-catenin-TCF4 complex in the enhancer region of the GLCE promoter. Electrophoretic mobility shift and supershift analyses confirmed binding of beta-catenin-TCF4 to these sequences of GLCE. GLCE expression in human colon carcinoma cell lines correlated with the degree of activation of the beta-catenin-TCF4 transactivation complex. Furthermore, ectopic expression of beta-catenin-TCF4 increased the GLCE transcript level and enhanced the rate of GlcA epimerization in HS. Ghiselli and Agrawal (2005) concluded that the beta-catenin-TCF4 transactivation pathway plays a major role in modulating GLCE expression, thus contributing to regulation of HS biosynthesis and its structural organization.
Batlle et al. (2002) showed that beta-catenin and TCF inversely control the expression of the EphB2 (600997)/EphB3 (601839) receptors and their ligand, ephrin B1 (EFNB1; 300035), in colorectal cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3 genes revealed that their gene products restrict cell intermingling and allocate cell populations within the intestinal epithelium. In EphB2/EphB3 null mice, the proliferative and differentiated populations intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their downward migratory path, but scattered along crypt and villus. The authors concluded that, in the intestinal epithelium, beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin B system.
Kawasaki et al. (2000) cloned a gene, ASEF (605216), whose protein product interacts directly with APC (611731). ASEF immunoprecipitates with beta-catenin; however, ASEF and beta-catenin do not interact directly, suggesting that ASEF, APC, and beta-catenin are found in the same complex in vivo. Kawasaki et al. (2000) suggested that the APC-ASEF complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function.
In addition to the inhibition of ubiquitination (see BTRC, 603482) of phosphorylated IKBA (164008), Neish et al. (2000) observed that phosphorylated CTNNB1 is not ubiquitinated in epithelial cells exposed to avirulent Salmonella.
Eastman and Grosschedl (1999) reviewed progress in understanding of how the activities of both beta-catenin and LEF1/TCF (153245) proteins are regulated. They summarized the interactions of beta-catenin and LEF1/TCF proteins, including a discussion of how cellular events can influence the stability of beta-catenin and its availability for association with LEF1/TCF proteins. Eastman and Grosschedl (1999) also discussed factors that influence beta-catenin activity independent of a Wnt signal.
Kang et al. (2002) showed that presenilin-1 (PS1; 104311) functions as a scaffold that rapidly couples beta-catenin phosphorylation through 2 sequential kinase activities independent of the Wnt-regulated axin (603816)/CK1-alpha (600505) complex. Presenilin deficiency resulted in increased beta-catenin stability in vitro and in vivo by disconnecting the stepwise phosphorylation of beta-catenin, both in the presence and absence of Wnt stimulation. These findings highlighted an aspect of beta-catenin regulation outside of the canonical Wnt-regulated pathway and a function of presenilin separate from intramembrane proteolysis.
Murase et al. (2002) transfected fluorescence-tagged chick beta-catenin into rat hippocampal neurons in culture. They found that, upon depolarization, beta-catenin moved from dendritic shafts into spines and increased its association with cadherins. This redistribution of beta-catenin was mimicked by addition of a tyrosine kinase inhibitor and prevented by addition of a phosphatase inhibitor. Transfection with a chick beta-catenin carrying a phosphorylation-preventing mutation of tyr654 (tyr654 to phe; Y654F) resulted in concentration of beta-catenin within spines, whereas transfection with a phosphorylation-mimicking mutation (tyr654 to glu; Y654E) resulted in beta-catenin accumulation in dendritic shafts. The Y654F-expressing neurons also exhibited a higher minifrequency and larger Psd95 (602887) and synapsin-1 (313440) clusters within synaptic spines.
Tetsu and McCormick (1999) showed that beta-catenin activated transcription from the cyclin D1 (CCND1; 168461) promoter. They identified promoter sequences related to consensus TCF/LEF-binding sites that were necessary for activation. p21 RAS (see 190020) further activated transcription of the cyclin D1 gene through sites within the promoter that bind the transcriptional regulators ETS (see 164720) or CREB (CREB1; 123810). Cells expressing mutant beta-catenin produced high levels of cyclin D1 mRNA and protein. Furthermore, expression of a dominant-negative form of TCF in colon cancer cells inhibited expression of cyclin D1 without affecting expression of other cyclins or cyclin-dependent kinases and caused cells to arrest in G1.
Lin et al. (2000) demonstrated that CCND1 is one of the targets of beta-catenin in breast cancer (114480) cells. They found that high beta-catenin activity correlated with poor patient prognosis and was a strong and independent prognostic factor in breast cancer. These studies indicated that beta-catenin can be involved in breast cancer formation and/or progression and may serve as a target for breast cancer therapy.
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.
Widlund et al. (2002) identified beta-catenin as a significant regulator of melanoma cell growth, with MITF (156845) as a critical downstream target. Disruption of the canonical Wnt pathway abrogated growth of melanoma cells, and constitutive overexpression of MITF rescued the growth suppression.
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-to-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. Beta-catenin then binds to and activates Lef1 transcription complexes that appear to act uncharacteristically by downregulating the gene encoding E-cadherin (192090), 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.
Jarvinen et al. (2006) found that expression of a stabilized form of beta-catenin in embryonic mouse oral and dental epithelium led to tooth buds that gave rise to dozens of teeth. The molar crowns, however, were typically simplified unicusped cones. Supernumerary teeth developed by a renewal process where new signaling centers, the enamel knots, budded off from the existing dental epithelium.
Hematopoietic stem cells (HSCs) have the ability to renew themselves and to give rise to all lineages of the blood. Reya et al. (2003) showed that the WNT signaling pathway has an important role in this process. Overexpression of activated beta-catenin expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF1/TCF reporter, which indicates that HSCs respond to WNT signaling in vivo. To demonstrate the physiologic significance of this pathway for HSC proliferation, Reya et al. (2003) showed that the ectopic expression of axin or a frizzled (603408) ligand-binding domain, inhibitors of the WNT signaling pathway, led to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs induced increased expression of HOXB4 (142965) and NOTCH1 (190198), genes previously implicated in self-renewal of HSCs. Reya et al. (2003) concluded that the WNT signaling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development.
In rat hippocampal neuronal cultures, Yu and Malenka (2003) found that increasing the intracellular levels of beta-catenin enhanced dendritic arborization. Although the effect did not require WNT-beta-catenin-dependent transcription, WNT was involved in enhanced dendritic arborization resulting from depolarization. Proteins that sequestered beta-catenin decreased dendritic branch tip number and total dendritic branch length. Yu and Malenka (2003) concluded that beta-catenin is a mediator of dendritic development.
To test whether nuclear translocation of beta-catenin is involved in axial identity and/or germ layer formation in 'pre-bilaterians,' Wikramanayake et al. (2003) examined the in vivo distribution, stability, and function of beta-catenin protein in embryos of the sea anemone Nematostella vectensis. Wikramanayake et al. (2003) found that N. vectensis beta-catenin is differentially stabilized along the oral-aboral axis, translocated into nuclei in cells at the site of gastrulation, and used to specify ectoderm, indicating an evolutionarily ancient role for this protein in early pattern formation.
Lee et al. (2004) demonstrated that WNT/beta-catenin signal activation in emigrating mouse neural crest stem cells had little effect on the population size and instead regulated fate decisions. Sustained beta-catenin activity in neural crest cells promoted the formation of sensory neural cells in vivo at the expense of virtually all other neural crest derivatives. Moreover, Lee et al. (2004) demonstrated that WNT is able to instruct early neural crest stem cells to adopt a sensory neuronal fate in a beta-catenin-dependent manner. Thus, Lee et al. (2004) concluded that the role of WNT/beta-catenin in stem cells is cell-type dependent.
Kleber et al. (2005) found that Bmp2 (112261) signaling antagonized the sensory fate-inducing activity of Wnt/beta-catenin. Wnt and Bmp2 acted synergistically to suppress differentiation and to maintain mouse neural crest stem cell marker expression and multipotency.
Brembeck et al. (2004) found that BCL9-2 (BCL9L; 609004) was involved in the switch between the adhesive and transcriptional functions of beta-catenin. The switch was initiated by tyrosine phosphorylation of beta-catenin, which favored BCL9-2 binding and precluded interaction with alpha-catenin.
By coimmunoprecipitation and tandem mass spectrometric analysis, Tian et al. (2004) found that 14-3-3-zeta is a beta-catenin-interacting protein. 14-3-3-zeta enhanced beta-catenin-dependent transcription by stabilizing beta-catenin in the cytoplasm. Furthermore, 14-3-3-zeta facilitated activation of beta-catenin by AKT (see AKT1; 164730) and colocalized with activated Akt in mouse intestinal stem cells. Tian et al. (2004) proposed that AKT phosphorylates beta-catenin, leading to 14-3-3-zeta binding and stabilization of beta catenin.
Guo et al. (2004) found that several Wnt genes, including Wnt4 (603490), Wnt14 (602863), and Wnt16 (606267), were expressed in overlapping and complementary patterns in developing mouse synovial joints, where Ctnnb1 protein level and transcription activity were upregulated. Removal of Ctnnb1 early in mesenchymal progenitor cells promoted chondrocyte differentiation and blocked the activity of Wnt14 in joint formation. Ectopic expression of an activated form of Ctnnb1 or Wnt14 in early differentiating chondrocytes induced ectopic joint formation both morphologically and molecularly. In contrast, genetic removal of Ctnnb1 in chondrocytes led to joint fusion. Guo et al. (2004) concluded that the Wnt/CTNNB1 signaling pathway is necessary and sufficient to induce early steps of synovial joint formation, and they suggested that WNT4, WNT14, and WNT16 may play redundant roles in synovial joint induction by signaling through the CTNNB1-mediated canonical Wnt pathway.
Kaplan et al. (2004) found that, in addition to its roles in cell-cell adhesion and Wnt-stimulated transcriptional activation, beta-catenin has a role in establishing bipolar mitotic spindles. During mitosis in mouse fibroblasts and HeLa cells, beta-catenin relocalized to mitotic spindle poles and to the midbody. Biochemical fractionation demonstrated the presence of beta-catenin in purified centrosome preparations. Reduction of beta-catenin by RNA interference led to failure of centrosomes to fully separate, resulting in a marked increase in the frequency of monoastral mitotic spindles.
Kim et al. (2005) reported that the downregulation of a metastasis suppressor gene, KAI1 (600623), in prostate cancer cells involves the inhibitory actions of beta-catenin, along with a reptin (TIP48; 604788) chromatin remodeling complex. This inhibitory function of beta-catenin-reptin requires both increased beta-catenin expression and recruitment of histone deacetylase activity. The coordinated actions of beta-catenin-reptin components that mediate the repressive state serve to antagonize a TIP60 (601409) coactivator complex that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. Kim et al. (2005) concluded that the molecular mechanisms underlying the antagonistic regulation of beta-catenin-reptin and the TIP60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-kappa-B (see 164011) target genes.
Essers et al. (2005) reported an evolutionarily conserved interaction of beta-catenin with FOXO transcription factors (e.g., 602681), which are regulated by insulin and oxidative stress signaling. In mammalian cells, beta-catenin binds directly to FOXO and enhances FOXO transcriptional activity. In C. elegans, loss of the beta-catenin BAR1 reduces the activity of the FOXO ortholog DAF16 in dauer formation and life span. Association of beta-catenin with FOXO was enhanced in cells exposed to oxidative stress. Furthermore, BAR1 was required for the oxidative stress-induced expression of the DAF16 target gene sod3 and for resistance to oxidative damage. Essers et al. (2005) concluded that their results demonstrated a role for beta-catenin in regulating FOXO function that is particularly important under conditions of oxidative stress.
Shah et al. (2006) stated that the signaling and oncogenic activity of beta-catenin can be repressed by activation of vitamin D receptor (VDR; 601769). Conversely, high levels of beta-catenin can potentiate the transcriptional activity of 1,25-dihydroxyvitamin D3. Shah et al. (2006) showed that the effects of beta-catenin on VDR activity are due interaction between the activator function-2 domain of VDR and the C terminus of beta-catenin.
Noubissi et al. (2006) demonstrated that beta-catenin stabilizes the mRNA encoding the F-box protein beta-TrCP1 (BTRCP1; 603482), and identified the RNA-binding protein CRDBP (608288) as a target of beta catenin/Tcf transcription factor. CRDBP binds to the coding region of BTRCP1 mRNA. Overexpression of CRDBP stabilized BTRCP1 mRNA and elevated BTRCP1 levels both in cells and in vivo, resulting in the activation of the Skp1-Cullin1-F-box protein (SCF)-BTRCP1 E3 ubiquitin ligase and in accelerated turnover of its substrates including I-kappa-B (see 164008) and beta-catenin. CRDBP is essential for the induction of both BTRCP1 and c-Myc (190080) by beta-catenin signaling in colorectal cancer cells. Noubissi et al. (2006) concluded that high levels of CRDBP that are found in primary human colorectal tumors exhibiting active beta-catenin/Tcf signaling implicates CRDBP induction in the upregulation of BTRCP1, in the activation of dimeric transcription factor NF-kappa-B, and in the suppression of apoptosis in these cancers.
Parakh et al. (2006) found that expression of beta-catenin lacking the N-terminal 90-amino acids that lead to its degradation significantly enhanced follicle-stimulating hormone (FSH; see 136350)-mediated induction of CYP19A1 (107910) and CYP11A1 (118485) mRNA. CYP19A1 transactivation by SF1 (NR5A1; 601516) required a functional interaction with beta-catenin and an intact beta-catenin-binding site. The beta-catenin-binding site was also critical for the synergistic actions of FSH and SF1 on CYP19A1. The actions of beta-catenin on CYP19A1 were dependent on hormone-induced cAMP cascades. Parakh et al. (2006) concluded that beta-catenin is essential for FSH/cAMP-regulated gene expression in ovary and that beta-catenin has a role in estrogen biosynthesis.
Moore et al. (2008) showed that epitope-tagged mammalian Mtgr1 (CBFA2T2; 603672), Mtg8 (RUNX1T1; 133435), and Mtg16 (CBFA2T3; 603870) interacted with human TCF4 in cotransfected COS-7 cells. Beta-catenin disrupted interaction of Mtg proteins with TCF4. When expressed in Xenopus embryos, Mtg family members inhibited Wnt-dependent axis formation and impaired the ability of beta-catenin or Lef1 to induce axis duplication. Furthermore, Myc was overexpressed in the small intestine of mice lacking Mtgr1. Moore et al. (2008) concluded that MTG proteins act downstream of beta-catenin in the Wnt signaling pathway.
Fungiform taste papillae form a regular array on the dorsal surface of the tongue. Taste buds arise from papilla epithelium and, unusual for epithelial derivatives, synapse with neurons, release neurotransmitters, and generate receptor and action potentials. Liu et al. (2007) demonstrated that Wnt-beta-catenin signaling is activated in developing fungiform placodes and taste bud cells. They showed that a dominant stabilizing mutation in epithelial beta-catenin causes massive overproduction of enlarged fungiform papillae and taste buds. Likewise, genetic deletion of epithelial beta-catenin or inhibition of Wnt-beta-catenin signaling by ectopic dickkopf-1 (Dkk1; 605189) blocked initiation of fungiform papilla morphogenesis. Ectopic papillae were innervated in the stabilizing beta-catenin mutant, whereas ectopic Dkk1 caused absence of lingual epithelial innervation. Thus, Wnt-beta-catenin signaling is critical for fungiform papilla and taste bud development. Altered regulation of the pathway may underlie evolutionary changes in taste papilla patterning.
Bahmanyar et al. (2008) found that stabilization of beta-catenin, mimicking mutations found in cancer, induced centrosome splitting, similar to ectopic NEK2 (604043) activation. They identified beta-catenin as a substrate and binding partner for NEK2 in vitro and in vivo and found that beta-catenin colocalized with the NEK2 substrates rootletin (CROCC; 615776) and CNAP1 (CEP2; 609689) between centrosomes. CNAP1 and rootletin were required for localization of beta-catenin between centrosomes in interphase, whereas beta-catenin had rootletin-independent binding sites on chromosomes at mitotic spindle poles. In response to ectopic expression of active NEK2 in interphase cells, rootletin was reduced at interphase centrosomes and beta-catenin localized to rootletin-independent sites on centrosomes, an event required for centrosome separation in mitosis.
Continuous turnover of epithelia is ensured by the extensive self-renewal capacity of tissue-specific stem cells. Similarly, epithelial tumor maintenance relies on cancer stem cells, which co-opt stem cell properties. In murine skin, follicular morphogenesis is driven by bulge stem cells that specifically express CD34 (142230). Malanchi et al. (2008) identified a population of cells in early epidermal tumors characterized by phenotype and functional similarities to normal bulge skin stem cells. This population contains cancer stem cells, which are the only cells with tumor initiation properties. Transplants derived from these cancer stem cells preserve the hierarchical organization of the primary tumor. Malanchi et al. (2008) described beta-catenin signaling as being essential in sustaining the cancer stem cell phenotype. Ablation of the beta-catenin gene results in the loss of cancer stem cells and complete tumor regression. In addition, Malanchi et al. (2008) provided evidence for the involvement of increased beta-catenin signaling in malignant human squamous cell carcinomas. Malanchi et al. (2008) concluded that because Wnt/beta-catenin signaling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate cancer stem cells and consequently eradicate squamous cell carcinomas.
To identify genes that both modulate beta-catenin activity and are essential for colon cancer cell proliferation, Firestein et al. (2008) conducted 2 loss-of-function screens in human colon cancer cells and compared genes identified in these screens with an analysis of copy number alterations in colon cancer specimens. One of these genes, cyclin-dependent kinase-8 (CDK8; 603184), which encodes a member of the mediator complex, is located at 13q12.13, a region of recurrent copy number gain in a substantial fraction of colon cancers. Firestein et al. (2008) showed that suppression of CDK8 expression inhibits proliferation in colon cancer cells characterized by high levels of CDK8 and beta-catenin hyperactivity. CDK8 kinase activity was necessary for beta-catenin-driven transformation and for expression of several beta-catenin transcriptional targets.
Morris et al. (2008) demonstrated that the transcription factor E2F1 (189971) is a potent and specific inhibitor of beta-catenin/T cell factor (TCF)-dependent transcription and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an APC (611731)/glycogen synthase kinase-3 (GSK3; see 606784)-independent manner, reducing the expression of key beta-catenin targets including c-MYC (190080). This interaction explains why colorectal tumors, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 (614041) intact. Remarkably, E2F1 activity is also repressed by CDK8, a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Morris et al. (2008) concluded that thus, by retaining RB1 and amplifying CDK8, colorectal tumor cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
Independently, Chassot et al. (2008) and Tomizuka et al. (2008) found that knockout of Rspo1 (609595) in mice resulted in at least partial sex reversal in females, but not males. Rspo1 was required for activation of beta-catenin and Wnt4 signaling for female sex determination.
In familial adenomatous polyposis (FAP), beta-catenin is stabilized constitutively, providing a permanent mitogenic signal to normally resting cells. This occurs when the second allele of APC (611731) is inactivated somatically. Kohler et al. (2009) described an APC domain, the beta-catenin inhibitory domain (CID), that is located between the second and third 20-amino acid beta-catenin-binding repeats and therefore was present in many truncated APC products found in human tumors. In truncated APC, the CID was absolutely necessary to downregulate the transcriptional activity and the level of beta-catenin, even when an axin/conductin binding site was present. The activity of the CID was dramatically reduced in several colon cancer cell lines and could be inhibited by shorter truncated APC lacking the CID. The authors concluded that CID is a direct target of the selective pressure acting on APC during tumorigenesis, and it explains the interdependence of both APC mutations in colorectal, duodenal, and desmoid tumors.
Huang et al. (2009) used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin (603816), the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, Huang et al. (2009) found that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase-1 (603303) and tankyrase-2 (607128). Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.
Gattinoni et al. (2009) reported that induction of Wnt/beta-catenin signaling by inhibitors of Gsk3b or by Wnt3a arrested mouse Cd8 (see 186910)-positive T-cell development into effector T cells capable of cytotoxicity or Ifng (147570) production. Instead, Wnt signaling promoted expression of Tcf7 and Lef1 and generation of self-renewing multipotent Cd8-positive memory stem cells capable of proliferation and antitumor activity. Gattinoni et al. (2009) concluded that Wnt signaling has a key role in maintaining the self-renewing stem cell-like properties of mature memory CD8-positive T cells.
Using RT-PCR and flow cytometric analysis, Zhao et al. (2010) demonstrated that mouse Tcf7 and Lef1 were highly expressed in naive T cells, downregulated in effector T cells, and upregulated in memory T cells. Memory Cd8-positive T cells expressing the p45 Tcf7 isoform and beta-catenin had enhanced Il2 (147680) production capacity and enhanced effector capacity to clear Listeria monocytogenes. Zhao et al. (2010) concluded that constitutive activation of the Wnt pathway favors memory CD8 T-cell formation during immunization, resulting in enhanced immunity upon a second encounter with the same pathogen.
Using a genetic approach, Driessens et al. (2010) found no evidence that the beta-catenin pathway regulates T-cell memory phenotype, in contrast with the findings of Gattinoni et al. (2009). The findings of Driessens et al. (2010) suggested that the generation of Cd8-positive memory stem cells observed by Gattinoni et al. (2009) with the use of Gsk3b inhibitors was not a consequence of activation of the beta-catenin pathway, but was rather due activation of another Gsk3b-dependent pathway. In a reply, Gattinoni et al. (2010) noted that others, including Zhao et al. (2010) and Jeannet et al. (2010), had also identified Wnt and beta-catenin as crucial factors in postthymic Cd8-positive T-cell differentiation and memory development. Using Western blot analysis, Gattinoni et al. (2010) showed that addition of Wnt3a or Gsk3b inhibitor stabilized beta-catenin in primed Cd8-positive mouse T cells.
Manicassamy et al. (2010) reported that the Wnt-beta-catenin signaling in intestinal dendritic cells regulates the balance between inflammatory versus regulatory responses in the gut. Beta-catenin in intestinal dendritic cells was required for the expression of antiinflammatory mediators such as retinoic acid metabolizing enzymes, interleukin-10 (124092), and transforming growth factor-beta (190180), and the stimulation of regulatory T cell induction while suppressing inflammatory effector T cells. Furthermore, ablation of beta-catenin expression in dendritic cells enhanced inflammatory responses and disease in a mouse model of inflammatory bowel disease. This, Manicassamy et al. (2010) concluded that beta-catenin signaling programs dendritic cells to a tolerogenic state, limiting the inflammatory response. Murphy (2011) commented that the deletion of beta-catenin in macrophages remains a caveat to the interpretation of Manicassamy et al. (2010) that Wnt signaling programs dendritic cells into a tolerogenic state. Development of strains expressing Cre in a more finely lineage-restricted pattern is necessary to resolve this issue. Manicassamy and Pulendran (2011) responded that beta-catenin-deficient dendritic cells are greatly impaired in inducing regulatory T cells, and induce enhanced TH17/TH1 responses. They agreed that assessing the relative importance of dendritic cells versus macrophages in intestinal tolerance awaits tools that permit the genetic deletion of the numerous dendritic cell and macrophage subsets in the intestine.
Yang et al. (2011) demonstrated in human cancer cells that EGFR (131550) activation induces translocation of PKM2, but not PKM1 (see 179050), into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of beta-catenin. This interaction is required for both proteins to be recruited to the CCND1 (168461) promoter, leading to HDAC3 (605166) removal from the promoter, histone H3 acetylation, and cyclin D1 expression. PKM2-dependent beta-catenin transactivation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development. In addition, positive correlations were identified between c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of beta-catenin phosphorylation and nuclear PKM2 were correlated with grades of glioma malignancy and prognosis. Yang et al. (2011) concluded that their findings revealed that EGF induces beta-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless and highlighted the essential nonmetabolic functions of PKM2 in EGFR-promoted beta-catenin transactivation, cell proliferation, and tumorigenesis.
Hoffmeyer et al. (2012) reported a molecular link between Wnt/beta-catenin signaling and the expression of the telomerase subunit Tert (187270). Beta-catenin-deficient mouse embryonic stem (ES) cells have short telomeres; conversely, ES cells expressing an activated form of beta-catenin (beta-catenin(deltaEx3/+)) have long telomeres. Hoffmeyer et al. (2012) showed that beta-catenin regulates Tert expression through the interaction with Klf4 (602253), a core component of the pluripotency transcriptional network. Beta-catenin binds to the Tert promoter in a mouse intestinal tumor model and in human carcinoma cells. Hoffmeyer et al. (2012) uncovered a theretofore unknown link between the stem cell and oncogenic potential whereby beta-catenin regulates Tert expression, and thereby telomere length, which could be critical in human regenerative therapy and cancer.
In mice, Takeo et al. (2013) showed that nail stem cells (NSCs) reside in the proximal nail matrix and are defined by high expression of keratin-14 (148066), keratin-17 (148069), and KI67 (MKI67; 176741). The mechanisms governing NSC differentiation are coupled directly to their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt (see 164820)-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, beta-catenin stabilization in the NSC region induced their regeneration. Takeo et al. (2013) concluded that their results established a link between nail stem cell differentiation and digit regeneration, and suggested that NSCs may have the potential to contribute to the development of novel treatments for amputees.
Focusing on skin development and oncogenic (Hras-G12V (190020.0001)-induced) hyperplasia, Beronja et al. (2013) carried out genomewide RNA interference-mediated screens in mice and uncovered theretofore unknown as well as anticipated regulators of embryonic epidermal growth. Among the top oncogenic screen hits were Mllt6 (600328) and the Wnt effector beta-catenin, which maintain Hras-G12V-dependent hyperproliferation. Beronja et al. (2013) also exposed beta-catenin as an unanticipated antagonist of normal epidermal growth, functioning through Wnt-independent intercellular adhesion.
Kode et al. (2014) showed that an activating mutation of beta-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML; 601626) with common chromosomal aberrations and cell-autonomous progression. Activated beta-catenin stimulates expression of the Notch (see NOTCH1, 190198) ligand Jag1 (601920) in osteoblasts. Subsequent activation of Notch signaling in hematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacologic inhibition of Notch signaling ameliorates AML and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes (see MDS, 614286) or AML, increased beta-catenin signaling and nuclear accumulation was identified in osteoblasts, and these patients showed increased Notch signaling in hematopoietic cells. Kode et al. (2014) concluded that their findings demonstrated that genetic alterations in osteoblasts can induce acute myeloid leukemia, identify molecular signals leading to this transformation, and suggested a potential novel pharmacotherapeutic approach to acute myeloid leukemia.
Using live imaging, Deschene et al. (2014) showed that activation of beta-catenin specifically within mouse hair follicle stem cells generates new hair growth through oriented cell divisions and cellular displacement. Beta-catenin activation is sufficient to induce hair growth independently of mesenchymal dermal papilla niche signals normally required for hair regeneration. Wildtype cells are co-opted into new hair growths by beta-catenin mutant cells, which non-cell autonomously activate Wnt signaling within the neighboring wildtype cells via Wnt ligands. Deschene et al. (2014) concluded that their study demonstrated a mechanism by which Wnt/beta-catenin signaling controls stem cell-dependent tissue growth non-cell autonomously.
In mice, Dias et al. (2014) showed that beta-catenin mediates proresilient and anxiolytic effects in the nucleus accumbens, mediated by D2-type medium spiny neurons. Using genomewide beta-catenin enrichment mapping, Dias et al. (2014) identified Dicer1 (606241) as a beta-catenin target gene that mediates resilience. Small RNA profiling after excising beta-catenin from nucleus accumbens in the context of chronic stress revealed beta-catenin-dependent microRNA regulation associated with resilience. Dias et al. (2014) concluded that these findings established beta-catenin as a critical regulator in the development of behavioral resilience, activating a network that includes DICER1 and downstream microRNAs. The authors stated that this evidence presented a foundation for the development of novel therapeutic targets to promote stress resilience.
Benham-Pyle et al. (2015) showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first YAP1 (606608) and then beta-catenin. Inhibition of YAP1- and beta-catenin-mediated transcription blocked cell cycle reentry and progression through G1 into S phase, respectively. Maintenance of quiescence, YAP1 nuclear exclusion, and beta-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Benham-Pyle et al. (2015) concluded that activation of YAP1 and beta-catenin may represent a master regulator of mechanical strain-induced cell proliferation, and that cadherins provide signaling centers required for cellular responses to externally applied force.
In an effort to evaluate the existence of a gut-vascular barrier (GVB), Spadoni et al. (2015) found that 4-kD fluorescent dextran freely diffused through mouse endothelial cells (ECs), but that 70-kD dextran did not, except in mice orally infected with Salmonella entrerica serovar Typhimurium. Pv1 (PLVAP; 607647), a marker of EC permeability, was not expressed in blood ECs in lamina propria, but it was upregulated in jejunal and ileum blood vessels after Salmonella infection at a time correlating with Salmonella dissemination to liver and spleen and with liver damage. Salmonella infection interfered with beta-catenin activation in ECs via bacterial Spi2. Induction of Ctnnb1 transcription in ECs resulted in loss of the ability of Salmonella to reach liver or spleen and a failure to upregulate Pv1 or to permit 70-kD dextran leakage. Confocal microscopy demonstrated the existence of a GVB in human gut that was also susceptible to disruption by Salmonella infection. The authors found that patients with celiac disease (see 212750) who had increased serum ALT (GPT; 138200) displayed higher PV1 expression than patients with normal ALT. Spadoni et al. (2015) concluded that, although the blood-brain barrier has a size exclusion of 500 Da, the GVB has a necessarily higher exclusion of 4 kD to allow for nutrient exploitation. Furthermore, both barriers use beta-catenin signaling to inhibit vascular permeability and bacterial penetration.
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, binds 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.
Graham et al. (2002) determined the crystal structure at 2.5-angstrom resolution of a complex between CTNNB1 and ICAT (607758), a protein that prevents interaction between CTNNB1 and TCF/LEF family transcription factors. ICAT contains a 3-helix bundle that binds armadillo repeats 10 to 12 and a C-terminal tail that, like TCF and E-cadherin, binds in the groove formed by armadillo repeats 5 to 9 of CTNNB1. Graham et al. (2002) showed that ICAT selectively inhibits CTNNB1/TCF binding in vivo, without disrupting CTNNB1/cadherin interactions. They concluded that it should be possible to design cancer therapeutics that inhibit CTNNB1-mediated transcriptional activation without interfering with cell adhesion.
Daniels and Weis (2002) determined the crystal structure of ICAT bound to the armadillo repeat domain of CTNNB1. ICAT contains an N-terminal helical domain that binds to repeats 11 and 12 of CTNNB1, and an extended C-terminal region that binds to repeats 5 to 10 in a manner similar to that of TCFs and other CTNNB1 ligands.
Neurodevelopmental Disorder with Spastic Diplegia and Visual Defects
In 3 patients with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), de Ligt et al. (2012) identified heterozygous loss-of-function mutations in the CTNNB1 gene (116806.0017-116806.0019). Two of the mutations were known to be de novo; in the third patient, the mutation was not inherited from the mother and the father's DNA was not available for testing.
By interrogating the DECIPHER database, Kharbanda et al. (2017) identified 11 patients with an inactivating mutation in the CTNNB1 gene (see, e.g., 116806.0021).
In a 15-month-old Chinese boy, who presented with ocular features consistent with exudative vitreoretinopathy (EVR; see 133780) but who was negative for mutation in EVR-associated genes, and who also exhibited microcephaly, developmental delay, and mild thumb adduction (NEDSDV), Li et al. (2017) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation (Q558X; 116806.0022) in the CTNNB1 gene.
In a 3-year-old Chinese boy with EVR, facial dysmorphism, and global developmental delay, Panagiotou et al. (2017) identified heterozygosity for a 1-bp insertion (116806.0023) in the CTNNB1 gene.
Exudative Vitreoretinopathy 7
In affected members of 2 unrelated families of Japanese origin with exudative vitreoretinopathy (EVR7; 617572), Panagiotou et al. (2017) identified heterozygosity for a missense mutation (R710C; 116806.0024) and a truncating mutation (116806.0025), respectively, in the CTNNB1 gene.
Somatic Mutations
Morin et al. (1997) found a total of 3 tumors that contained CTNNB1 mutations that altered potential phosphorylation sites. Each mutation was somatic and appeared to affect only 1 of the 2 CTNNB1 alleles. Causative mutations were heterozygous. The authors hypothesized that the mutations might exert a dominant effect, rendering a fraction of cellular beta-catenin insensitive to APC-mediated downregulation. Thus, disruption of APC-mediated regulation of beta-catenin/TCF-regulated transcription is critical for colorectal tumorigenesis. This is most commonly achieved by recessive inactivating mutations of both APC alleles, but can also be achieved by dominant mutations of CTNNB1 that render CRT insensitive to the effects of wildtype APC.
Ilyas et al. (1997) found 5 different mutations in 21 colorectal cancer cell lines (26%) from 19 patients: a 3-bp deletion from codon 45 and single-nucleotide missense mutations involving codons 33, 183, 245, and 287. All 23 cell lines studied had full-length beta-catenin protein that was detectable by Western blotting and that coprecipitated with E-cadherin. In 3 of the cell lines with CTNNB1 mutations, complexes of beta-catenin with alpha-catenin and APC were detectable; in 2 other cell lines, complexes were not detected.
Rubinfeld et al. (1997) detected abnormally high amounts of beta-catenin in 7 of 26 human melanoma cell lines. Unusual messenger RNA splicing and missense mutations in the CTNNB1 gene that result in stabilization of the protein were identified in 6 of the 7 lines, and the APC gene was altered or missing in 2 others. In the APC-deficient cells, ectopic expression of wildtype APC eliminated the excess beta-catenin. Cells with stabilized beta-catenin contained a constitutive beta-catenin/Lef1 complex. Thus, Rubinfeld et al. (1997) concluded that genetic defects that result in upregulation of beta-catenin may play a role in melanoma progression.
In a review of hereditary cancer syndromes, Fearon (1997) presented a useful diagram illustrating how the APC protein regulates beta-catenin levels in normal cells and how mutations in APC and CTNNB in cancer cell genes deregulate cell growth via T-cell transcription factor-7-like-2.
Chan et al. (1999) studied 16 human pilomatricomas (132600) and found CTNNB1 mutations in 12 of them. The mutations occurred in the amino-terminal segment, normally involved in phosphorylation-dependent, ubiquitin-mediated degradation, and thus are beta-catenin-stabilizing mutations. The authors concluded that the 75% mutation rate directly implicates beta-catenin/LEF misregulation as the major cause of hair matrix cell tumorigenesis in humans.
Sagae et al. (1999) analyzed 61 primary ovarian carcinomas (167000), consisting of 49 nonendometrioid-type tumors and 12 endometrioid tumors, for genetic alteration of the CTNNB1 gene. In 5 carcinomas, including 4 (33%) of the endometrioid-type tumors and 1 (14%) of 7 mucinous-type tumors, they found 3 somatic CTNNB1 mutations (see, e.g., 116806.0012). All of the mutations caused alterations at the serine/threonine residues that are potential sites of phosphorylation of GSK3-beta (GSK3B; 605004). Immunohistochemical studies were performed in 27 of the 61 ovarian carcinomas. Expression of both nuclear and cytoplasmic beta-catenin was demonstrated in 4 of these 27 ovarian carcinomas for which tissue samples were available for examination. Sagae et al. (1999) concluded that the CTNNB1 mutations at potential GSK3B phosphorylation sites result in accumulation of beta-catenin protein within cells and its translocation to nuclei.
Wright et al. (1999) identified somatic mutations within exon 3 of the CTNNB1 gene in 10 of 63 (16%) endometrioid ovarian carcinomas. The mutations all resulted in missense changes within the GSK3-beta consensus site.
Hepatoblastoma, a rare malignant tumor of the liver that occurs in children at an average age of 2 to 3 years, represents the most frequent malignant liver tumor in childhood. Although most cases are sporadic, the incidence is highly elevated in patients with familial APC. These patients carry germline mutations of the APC gene, which controls the degradation of the CTNNB1 gene product after its NH2-terminal phosphorylation on serine/threonine residues. APC, as well as CTNNB1, is a central effector of the growth-promoting 'wingless' signaling pathway in development. To determine whether this pathway is involved in the pathogenesis of sporadic hepatoblastomas, Koch et al. (1999) examined 52 biopsies and 3 cell lines from sporadic hepatoblastomas for mutations in the APC and CTNNB1 genes. In 48% of sporadic hepatoblastomas they found CTNNB1 mutations (116806.0003-116806.0005). The mutations affected exon 3, which encodes the degradation targeting box of CTNNB1, and led to accumulation of intracytoplasmic and nuclear beta-catenin protein. In all, 11 point mutations and 5 small interstitial deletions of 24 to 102 bp were found. Eight point mutations abolished serine or threonine phosphorylation sites. An increased transcriptional activity was demonstrated in vitro for CTNNB1 forms carrying similar mutations in exon 3.
A major function of APC is the downregulation of beta-catenin, a transcription-activating protein with oncogenic potential. Molecular genetic studies suggest that inactivation of the APC tumor suppressor may be involved in hepatoblastoma tumorigenesis. In an ongoing immunohistochemical study of beta-catenin expression in sporadic cases of tumor types that are associated with adenomatous polyposis coli, Blaker et al. (1999) observed increased beta-catenin levels in the cytoplasm and in the nuclei of 3 hepatoblastomas. Sequencing of exon 3 of the CTNNB1 gene revealed an activating mutation in one of the tumor samples (116806.0003). Thus, beta-catenin accumulation may play a role in the development of hepatoblastoma and heterozygous activating mutations of the CTNNB1 gene may substitute for biallelic APC inactivation in this tumor type.
Legoix et al. (1999) found an activating beta-catenin mutation in exon 3 in 18% of cases of hepatocellular carcinoma. Among tumors lacking a beta-catenin mutation, no APC mutation had been detected in a subset of 30 cases tested. The correlation between beta-catenin mutation status and chromosome segment deletions was studied on a set of 48 hyperploid tumors. Chromosome 1p, 4q, and 16p deletions were significantly associated with the absence of beta-catenin mutation. The results suggested the existence of 2 mechanisms of carcinogenesis: first, a beta-catenin activating mutation associated with a low rate of loss of heterozygosity; a second, operating in a context of chromosomal instability, would involve tumor suppressor genes.
Huang et al. (2000) screened 46 sporadic medulloblastomas for the presence of mutations in genes of the Wnt signaling pathway (APC and beta-catenin). Four tumors were found to have miscoding beta-catenin mutations, 3 of which were located at codon 33 (ser33 to phe; 116806.0007).
In desmoid tumor tissue (see 135290), Shitoh et al. (1999) identified a somatic thr41-to-ala mutation (116806.0003) in the beta-catenin gene.
Among 166 lung cancers (90 primary tumors and 76 cell lines), 1 blastoma, and 10 malignant mesotheliomas (156240) (2 primary tumors and 8 cell lines), Shigemitsu et al. (2001) identified 4 alterations in exon 3 of the CTNNB1 gene. Among 10 malignant mesotheliomas, they identified in 1 cell line a homozygous deletion of the entire gene except for exon 1.
Wheeler et al. (2002) examined the possible contribution of beta-catenin to sporadic small intestinal adenocarcinoma. Beta-catenin protein expression was assessed immunohistochemically in a total of 21 nonfamilial, nonampullary small intestinal adenocarcinomas. Ten (48%) showed decreased expression at the cell membrane and increased nuclear staining; this contrasted with the usual pattern of protein expression in normal colonic epithelium, where nuclear expression is undetectable using immunohistochemical techniques. The authors also screened the mutation cluster region of the APC gene and found no mutations, leading them to suggest that increased nuclear localization of beta-catenin may reflect gain-of-function mutation, similar to that seen in up to 25% of colorectal cancers (Ilyas et al., 1997).
As noted, inactivating mutations of the APC gene or activating mutations of the CTNNB1 gene initiate colorectal neoplasia. To address the biochemical and physiologic effects of mutant beta-catenin, Chan et al. (2002) disrupted either the mutant or wildtype CTNNB1 allele in a human colorectal cancer cell line. Cells with only wildtype beta-catenin had decreased colony-forming ability when plated at low density, although their growth was similar to that of parental cells when passaged under routine conditions. Immunohistochemistry and cell-fractionation studies suggested that mutant beta-catenin activity was distinguished primarily by cellular localization and not by protein degradation. Unexpectedly, they found that mutant beta-catenin bound less well to E-cadherin (CDH1; 192090) than did wildtype beta-catenin, and the membranous localization of wildtype and mutant beta-catenin was accordingly distinct. These findings were considered to pose serious challenges to the current models of APC/beta-catenin function.
Moreno-Bueno et al. (2001) analyzed the expression pattern of beta-catenin in normal anagen hair follicles and in 40 human pilomatrixomas by immunohistochemistry. In 11 of these tumors they also studied exon 3 beta-catenin gene mutations by PCR and direct sequencing. As these mutations have been related to a replication error (RER) phenotype in other tumor types, Moreno-Bueno et al. (2001) explored whether or not this association also occurs in pilomatrixomas. Beta-catenin was expressed in the cell membranes of the outer and inner root sheaths and in matrix cells located at the base and periphery of the hair follicle bulb. However, central matrix cells that differentiate into cortical cells, cortical, and cuticular cells expressed beta-catenin in the nucleus, suggesting a role in signal transduction. In addition, some fibroblasts of the dermal papilla also showed nuclear expression of beta-catenin. All 40 analyzed pilomatrixomas showed intense nuclear and cytoplasmic beta-catenin expression in proliferating matrix (basaloid) cells. In areas of maturation, transitional cells mainly showed cytoplasmic and membranous expression of beta-catenin, while only a few cells retained nuclear expression. Shadow or ghost cells did not show beta-catenin expression. Three of 11 tumors (26%) had beta-catenin mutations. All 3 had the same heterozygous missense mutation: a G-to-T change affecting the first nucleotide at codon 32 (116806.0016). None of the 11 tumors studied had a positive RER phenotype. Moreno-Bueno et al. (2001) concluded that the Wnt/Ctnnb1/Tcf-Lef pathway is activated in normal matrix cells of the hair follicle to induce differentiation to the hair shaft. Additionally, the beta-catenin mutation in matrix cells of the hair follicle stabilizes beta-catenin protein, which translocates into the nucleus, where it activates gene transcription together with lymphoid enhancer factor-1 (153245)-producing pilomatrixoma. These mutations occur without an underlying defect in DNA mismatch repair.
Teo et al. (2015) described 3 women with hyperaldosteronism, 2 who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding beta-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR (152790) and GNRHR (138850) at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulated Wnt activation and caused adrenocortical cells to dedifferentiate toward their common adrenal-gonadal precursor cell type.
An effector of intercellular adhesion, beta-catenin also functions in Wnt signaling, associating with Lef1/Tcf DNA-binding proteins to form a transcription factor. Gat et al. (1998) reported that this pathway also operates in keratinocytes and that mice expressing beta-catenin controlled by an epidermal promoter undergo a process resembling de novo hair morphogenesis. The new follicles form sebaceous glands and dermal papilla, normally established only in embryogenesis. As in embryologically initiated hair germs, transgenic follicles induce Lef1, but follicles are disoriented and defective in Sonic hedgehog polarization. Additionally, proliferation continues unchecked, resulting in 2 types of tumors (epithelioid cysts and trichofolliculomas) that are also found in humans. Older transgenic mice develop pilomatricomas. These findings suggested that transient beta-catenin stabilization may be a key player in the epidermal signal leading to hair development and implicated aberrant beta-catenin activation in hair tumors.
Harada et al. (1999) found that targeted deletion of exon 3 in mice, which encodes serines and threonines phosphorylated by GSK3-beta, caused adenomatous intestinal polyps resembling those in Apc knockout mice. Some nascent microadenomas were also found in the colon.
To study the role of beta-catenin in skin development, Huelsken et al. (2001) introduced a conditional mutation of the gene in the epidermis and hair follicles of mice using Cre/loxP technology. When beta-catenin was mutated during embryogenesis, formation of placodes that generate hair follicles was blocked. The authors showed that beta-catenin is required genetically downstream of Tabby (300450) and downless (EDAR; 604095) and upstream of bone morphogenetic proteins (see 112262) and Shh (600725) in placode formation. If beta-catenin was deleted after hair follicles had formed, hair was completely lost after the first hair cycle. Further analysis demonstrated that beta-catenin is essential for fate decisions of skin stem cells: in the absence of beta-catenin, stem cells failed to differentiate into follicular keratinocytes and instead adopted an epidermal fate.
Saadi-Kheddouci et al. (2001) found that transgenic mice that overproduced an oncogenic form of beta-catenin in the epithelial cells of the kidney developed severe polycystic lesions soon after birth.
To examine whether activating beta-catenin signaling could regulate mammalian brain development, Chenn and Walsh (2002) developed transgenic mice overexpressing an amino-terminal truncated form of beta-catenin fused at the carboxyl-terminal with green fluorescent protein in neuroepithelial precursors. The mice developed enlarged brains with increased cerebral cortical surface area and folds resembling sulci and gyri of higher mammals. Brains from transgenic animals have enlarged lateral ventricles lined with neuroepithelial precursor cells, reflecting an expansion of the precursor population. Compared with wildtype precursors, a greater proportion of transgenic precursors reenter the cell cycle after mitosis. Chenn and Walsh (2002) concluded that their results showed that beta-catenin can function in the decision of precursors to proliferate or differentiate during mammalian neuronal development and suggested that beta-catenin can regulate cerebral cortical size by controlling the generation of neuronal precursor cells.
Lickert et al. (2002) conditionally inactivated the beta-catenin gene in cells of structures that exhibit organizer functions in mouse embryos: the visceral endoderm, the node, the notochord, and the definitive endoderm. Mesoderm formation was not affected in mutant embryos, but the node was missing, patterning of the head and trunk was affected, and no notochord or somites were formed. Deletion of beta-catenin in the definitive endoderm led to the formation of multiple hearts along the anterior-posterior axis of the embryo. Ectopic hearts developed in parallel with the normal heart in regions of ectopic Bmp2 expression. Lickert et al. (2002) concluded that ablation of beta-catenin in embryonic endoderm changes cell fate from endoderm to precardiac mesoderm.
By conditional gene ablation in mice, Soshnikova et al. (2003) found that Wnt signaling is a key regulator of formation of the apical ectodermal ridge (AER) and the dorsal-ventral axis of the limbs. They generated compound mutants and showed that beta-catenin acts downstream of BMP receptor-1A (BMPR1A; 601299) in AER induction, but upstream or parallel in dorsal-ventral patterning. Soshnikova et al. (2003) concluded that AER formation and dorsal-ventral patterning of limbs is tightly controlled by Wnt/beta-catenin and BMP receptor signaling.
In mice bred to have T cells lacking Ctnnb1, Xu et al. (2003) observed a substantial reduction in the number of splenic T cells. Splenic T cells from these mice responded poorly to T-cell receptor (TCR) stimulation but showed no signs of enhanced cell death. Analysis of thymic development suggested that Ctnnb1 deletion affected pre-TCR signaling in double-negative thymocytes and impaired T-cell development at the level of the beta selection checkpoint.
Day et al. (2005) found that ectopic canonical Wnt signaling led to enhanced ossification and suppression of chondrocyte formation in mice. Conversely, genetic inactivation of beta-catenin caused ectopic formation of chondrocytes at the expense of osteoblast differentiation during both intramembranous and endochondral ossification.
By conditional deletion of beta-catenin in mouse limb and head mesenchyme, Hill et al. (2005) found that beta-catenin was required for osteoblast lineage differentiation. Osteoblast precursors lacking beta-catenin were blocked in differentiation and developed into chondrocytes. Further experiments showed that beta-catenin activity was necessary and sufficient to repress the differentiation of mesenchymal cells into skeletal precursors.
Glass et al. (2005) engineered mice harboring either gain-of-function or loss-of-function beta-catenin mutations targeted to osteoblasts. These mice developed high and low bone mass phenotypes, respectively, caused primarily by modification of bone resorption. Molecular analysis revealed that canonical Wnt signaling controlled this process by regulating expression of Opg (TNFRSF11B; 602643) within osteoblasts. Glass et al. (2005) concluded that canonical Wnt signaling in osteoblasts is a major negative regulator of bone resorption.
Using a gerbil model of gastritis and gastric cancer, Franco et al. (2005) showed that in vivo adaptation of Helicobacter pylori by multiple passages allowed a more rapid and reproducible induction of gastric dysplasia and adenocarcinoma. The oncogenic H. pylori strain selectively activated Ctnnb in gastric epithelia in a manner dependent on translocation of bacterial CagA into host epithelial cells. Ctnnb nuclear accumulation was increased in gastric epithelium from gerbils infected with the carcinogenic H. pylori strain, as well as in persons carrying Cag-positive versus Cag-negative bacterial strains or uninfected persons. Franco et al. (2005) proposed that H. pylori-induced dysregulation of CTNNB may explain, at least in part, the augmented risk of gastric cancer after infection with this pathogen.
Zamora et al. (2007) found that conditional deletion of beta-catenin in mouse proepicardium led to impaired formation of coronary arteries, whereas the venous system and microvasculature of mutant mice were normal. Mutant mice exhibited impaired epicardial development, including failed expansion of the subepicardial space, blunted invasion of the myocardium, and impaired differentiation of epicardium-derived mesenchymal cells into coronary smooth muscle cells.
After amputation, freshwater planarians properly regenerate a head or tail from the resulting anterior or posterior wound. Gurley et al. (2008) found that in the planarian Schmidtea mediterranea, RNA interference (RNAi) of beta-catenin or dishevelled (601365) causes the inappropriate regeneration of a head instead of a tail at posterior amputations. Conversely, RNAi of the beta-catenin antagonist adenomatous polyposis coli (APC; 611731) results in the regeneration of a tail at anterior wounds. In addition, the silencing of beta-catenin is sufficient to transform the tail of uncut adult animals into a head. Gurley et al. (2008) suggested that beta-catenin functions as a molecular switch to specify and maintain anteroposterior identity during regeneration and homeostasis in planarians.
Petersen and Reddien (2008) independently performed experiments similar to those described by Gurley et al. (2008) and identified a single gene, which they called Smed-beta-catenin, that defines the character of the anterioposterior axis throughout the Bilateria and specifies regeneration polarity in planarians.
Liu et al. (2009) ablated beta-catenin specifically in the Sf1 (NR5A1; 601516)-positive population of mouse somatic cells and showed that beta-catenin was present in gonads of both sexes but was necessary only for ovarian differentiation but dispensable for testis development. Loss of beta-catenin in fetal testes did not affect Sertoli cell differentiation, testis morphogenesis, or masculinization of the embryos. However, there were molecular and morphologic defects in ovaries lacking beta-catenin, including formation of testis-specific coelomic vessel, appearance of androgen-producing adrenal-like cells, and loss of female germ cells. These phenotypes were strikingly similar to those found in the Rspo1 (609595)- and Wnt4 (603490)-knockout ovaries. In the absence of beta-catenin, expression of Wnt4 was downregulated, while that of Rspo1 was not affected, placing beta-catenin as a component in between Rspo1 and Wnt4.
Adrenocortical carcinoma (ADCC; 202300) is a rare but aggressive cancer. Constitutive activation of beta-catenin is the most frequent alteration in benign and malignant adrenocortical tumors in humans. Berthon et al. (2010) showed that constitutive activation of beta-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cell hyperplasia as well as dysplasia of the cortex and medulla. Over 17 months, transgenic adrenals developed malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion. These oncogenic events were accompanied by ectopic differentiation of glomerulosa at the expense of fasciculata cells, which caused primary hyperaldosteronism. Berthon et al. (2010) concluded that constitutively active beta-catenin is an adrenal oncogene, which may trigger benign aldosterone-secreting tumor development and promote malignancy.
Tucci et al. (2014) identified a mouse mutant, designated 'batface' (Bfc), resulting from a heterozygous T653K mutation in the C-terminal armadillo repeat of the Ctnnb1 gene. Mutant mice had craniofacial abnormalities, including shortened anteroposterior axis, broad face, and shortened nasal length, as well as brain morphologic changes, such as larger deep brain structures, reduced cerebellar and olfactory bulb volume, and underdeveloped corpus callosum. Mutant mice demonstrated behavioral and cognitive abnormalities, including defects in prepulse inhibition, motor deficits, decreased vocalization complexity, and decreased hippocampal-dependent memory performance. In vitro cellular studies showed that the T653K mutation disrupted the association between Ctnnb1 and cadherin, consistent with a dominant-negative effect. Brains of heterozygous mutant mice initially showed increased length and number of neurons, but later showed decreased dendritic branching compared to controls. Knockdown of Ctnnb1 using siRNA caused a similar decrease in neuritic length and number of processes in wildtype neurons, suggesting that the T653K mutation also causes a loss of function. Electrophysiologic studies of mutant neurons indicated higher excitability of neural networks and less efficient functional connectivity compared to wildtype. The findings indicated that CTNNB1 plays key roles in many aspects of neurodevelopment and synaptic function.
To understand how CTNNB1 deficiency may contribute to autism spectrum disorder (ASD; 209850), Dong et al. (2016) generated mice with conditional deletion of Ctnnb1 in parvalbumin (PV) interneurons. The mutant mice showed increased anxiety, but there was no change in motor function. Mice lacking Ctnnb1 in PV interneurons had impaired object recognition and social interactions and elevated repetitive behaviors, mimicking the core symptoms of patients with ASD. On the other hand, Ctnnb1 deletion in PV interneurons enhanced spatial memory. Immunohistochemical analysis of mice sacrificed after stimulation, to assure an awake state, demonstrated a reduction of Fos (164810) activity in the prefrontal cortex, but not in the hippocampus, dentate gyrus, or amygdala. Dong et al. (2016) suggested that their findings may have implications for the treatment of ASD due to deficiency of CTNNB1 or other proteins in Wnt pathway.
In 2 colorectal cancer (see 114500) cell lines that expressed full-length APC, yet had escaped inhibition of transcriptional activation mediated by beta-catenin and TCF7L2, Morin et al. (1997) found a mutation in a downstream component of the APC tumor suppressor pathway, namely in the CTNNB1 gene. Each tumor line had a different mutation: a 3-bp deletion that removed an amino acid (ser45) in one and a C-to-A missense mutation that changed ser33 to tyr (116806.0002) in the other. Analysis of paraffin-embedded archival tissue from the first patient confirmed the somatic nature of this mutation and its presence in the primary tumor before culture. Both mutations affected serines that have been implicated in the downregulation of beta-catenin through phosphorylation.
See 116806.0001 and Morin et al. (1997). One of the 5 point mutations found by Ilyas et al. (1997) in colorectal cancer (see 114500) cell lines was a ser33-to-tyr mutation due to a C-to-A transversion in exon 3 of the CTNNB1 gene. The mutation was present in heterozygous form.
Chan et al. (1999) identified this mutation in 2 of 16 pilomatricomas (132600).
In 6 sporadic hepatoblastomas (see 114550), Koch et al. (1999) found an A-to-G transition in codon 41 of the CTNNB1 gene, resulting in a thr41-to-ala (T41A) substitution. (Iwao et al. (1998) described codon 41 mutations in sporadic colorectal carcinomas.) The ages of the patients with the T41A mutation and hepatoblastoma ranged from 4 to 27 months.
In a hepatoblastoma, Blaker et al. (1999) demonstrated intense cytoplasmic beta-catenin staining compared to adjacent normal liver tissue and accumulation of beta-catenin in the tumor cell nuclei. Furthermore, the tumor in one case was found to be heterozygous for an A-to-G transition converting codon 41 from ACC (thr) to GCC (ala). Legoix et al. (1999) found this same mutation in 3 cases of hepatocellular carcinoma. Rather than being childhood cases, these were adults (mean age 58 years; range, 27 to 76 years). In the group of 98 cases, many of the subjects were alcoholics.
Shitoh et al. (1999) identified a somatic T41A mutation in the CTNNB1 gene within desmoid tumor tissue derived from a patient with sporadic disease (see 135290).
In 2 sporadic hepatoblastomas (see 114550), Koch et al. (1999) found a change of codon 32 from GAC to TAC, resulting in an asp32-to-tyr substitution. The ages of the patients were 19 and 30 months.
Chan et al. (1999) identified this mutation in 1 of 16 pilomatricomas (132600).
In 3 cases of sporadic hepatoblastoma (see 114550), Koch et al. (1999) found that the tumors carried a gly34-to-val substitution in beta-catenin due to a change of codon 34 from GGA to GTA. The ages of the patients varied from 10 to 19 months.
In 1 of 16 pilomatricomas (132600) studied, Chan et al. (1999) found an A-to-G transition in the CTNNB1 gene resulting in an asp-to-gly substitution at codon 32 of beta-catenin.
In 2 of 16 pilomatricomas (132600) examined, Chan et al. (1999) identified a C-to-T transition in the CTNNB1 gene resulting in a ser-to-phe substitution at codon 33 (S33F) of beta-catenin.
Huang et al. (2000) identified the S33F mutation in the CTNNB1 gene in 3 of 46 sporadic medulloblastomas (155255).
In 3 of 16 pilomatricomas (132600) studied, Chan et al. (1999) identified a G-to-A transition in the CTNNB1 gene resulting in a gly-to-glu substitution at codon 34 of beta-catenin.
In 1 of 16 pilomatricomas (132600) examined, Chan et al. (1999) identified a C-to-G transversion in the CTNNB1 gene, which resulted in a ser-to-cys substitution at codon 37 of beta-catenin.
In 1 of 16 pilomatricomas (132600) studied, Chan et al. (1999) identified a C-to-T transition in the CTNNB1 gene resulting in a ser-to-phe substitution at codon 37 of beta-catenin.
In 1 of 16 pilomatricomas (132600) examined, Chan et al. (1999) identified a C-to-T transition in the CTNNB1 gene resulting in a thr-to-ile substitution at codon 41 of beta-catenin.
One of 3 mutations in exon 3 of the CTNNB1 gene detected by Sagae et al. (1999) in epithelial ovarian carcinoma (167000) was a ser37-to-cys (S37C) missense mutation. The tumor showed endometrioid histology.
In 4 cases of hepatocellular carcinoma (114550), Legoix et al. (1999) found a change in codon 45 of the CTNNB1 gene from TCT (ser) to TTT (phe). In 4 other cases, there was a ser45-to-pro mutation (116806.0014).
In 4 cases of hepatocellular carcinoma (114550), Legoix et al. (1999) found a change in codon 45 of the CTNNB1 gene from TCT (ser) to CCT (pro).
In 3 of 11 pilomatricomas studied, Moreno-Bueno et al. (2001) found a heterozygous G-to-T transversion in exon 3 of the CTNNB1 gene, which resulted in an asp32-to-tyr (D32Y) amino acid change.
In a 29-year-old woman with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), de Ligt et al. (2012) identified a 4-bp deletion (1272_1275del) in the CTNNB1 gene, resulting in a frameshift (Ser425ThrfsTer11). This mutation was not identified in either parent. The authors noted that this patient also had a heterozygous missense mutation in the ARFGEF2 gene (605371; R802Q). Mutations in the ARFGEF2 gene are known to cause intellectual disability but are inherited in an autosomal recessive manner.
In an individual with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), de Ligt et al. (2012) identified a de novo heterozygous nonsense mutation in the CTNNB1 gene, arg515-to-ter (R515X).
In an individual with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), de Ligt et al. (2012) identified a heterozygous nonsense mutation in the CTNNB1 gene, gln309-to-ter (Q309X). The mutation was not present in the patient's mother, but the father's DNA was not available for testing.
In an individual with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), Tucci et al. (2014) identified a de novo heterozygous 1-bp duplication (705dup), resulting in a frameshift and premature termination (Gly236ArgfsTer35).
In 2 unrelated patients with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), Kharbanda et al. (2017) identified heterozygosity for a de novo c.1603C-T transition in the CTNNB1 gene, resulting in an arg535-to-ter (R535X) substitution.
In a 15-month-old Chinese boy with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), Li et al. (2017) identified heterozygosity for a de novo c.1672C-T transition in exon 11 of the CTNNB1 gene, resulting in an gln558-to-ter (Q558X) substitution.
In a 3-year-old Chinese boy with neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; 615075), Panagiotou et al. (2017) identified heterozygosity for a de novo 1-bp insertion (c.1434_1435insC, NM_001904.3) in exon 9 of the CTNNB1 gene, causing a frameshift predicted to result in a premature termination codon (Glu479ArgfsTer18). The mutation was not found in his unaffected parents or in the dbSNP, Exome Variant Server, or ExAC databases.
In affected members of a 3-generation Japanese family (F410) with exudative vitreoretinopathy (EVR7; 617572), Panagiotou et al. (2017) identified heterozygosity for a c.2128C-T transition (c.2128C-T, NM_001904.3) in exon 14 of the CTNNB1 gene, resulting in an arg710-to-cys (R710C) substitution at a highly conserved residue within the C-terminal domain. The mutation, which was also present in the 9-year-old unaffected brother of the proband, was not found in the dbSNP, Exome Variant Server, or ExAC databases.
In 3 affected members of a 3-generation Hawaiian family (F258) of Japanese origin with exudative vitreoretinopathy (EVR7; 617572), Panagiotou et al. (2017) identified heterozygosity for a 16-bp duplication (c.2142_2157dupTAGCTATCGTTCTTTT, NM_001904.3) in exon 15 of the CTNNB1 gene, causing a frameshift resulting in a premature termination codon (H720X) within the C-terminal domain. The mutation segregated with disease in the family and was not found in the dbSNP, Exome Variant Server, or ExAC databases.
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