Cellular and Molecular Life Sciences

, Volume 68, Issue 15, pp 2493–2498 | Cite as

Alpha T-catenin (CTNNA3): a gene in the hand is worth two in the nest

  • James D. Smith
  • Maria H. Meehan
  • John Crean
  • Amanda McCannEmail author
Visions and Reflections


Alpha-T-Catenin (CTNNA3) is a key protein of the adherens junctional complex in epithelial cells playing a crucial role in cellular adherence. What makes this gene particularly interesting is that it is located within a common fragile site, is epigenetically regulated, is transcribed through multiple promoters, and generates a variety of alternate transcripts. Finally, CTNNA3 has a nested gene (LRTMM3) embedded within its genomic context transcribed in the opposite direction. Apart from the complexity of its regulation, alterations in both CTNNA3 and LRTMM3 are implicated in human disease.


CTNNA3 LRTMM3 Alpha-T-catenin Adherens junction Nested gene 


  1. 1.
    Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI (2005) Alpha-catenin is a molecular switch that binds E-cadherin-beta-catenin and regulates actin-filament assembly. Cell 123:903–915PubMedCrossRefGoogle Scholar
  2. 2.
    Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ (2005) Deconstructing the cadherin–catenin–actin complex. Cell 123:889–901PubMedCrossRefGoogle Scholar
  3. 3.
    Janssens B, Mohapatra B, Vatta M, Goossens S, Vanpoucke G, Kools P, Montoye T, Van Hengel J, Bowles NE, Van Roy F, Towbin JA (2003) Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy. Hum Genet 112:227–236PubMedGoogle Scholar
  4. 4.
    Janssens B, Goossens S, Staes K, Gilbert B, Van Hengel J, Colpaert C, Bruyneel E, Mareel M, Van Roy F (2001) AlphaT-catenin: a novel tissue-specific beta-catenin-binding protein mediating strong cell–cell adhesion. J Cell Sci 114:3177–3188PubMedGoogle Scholar
  5. 5.
    Oudejans C, Mulders J, Lachmeijer AM, Van Dijk M, Konst AA, Westerman BA, Van Wijk IJ, Leegwater PA, Kato HD, Matsuda T, Wake N, Dekker GA, Pals G, ten Kate LP, Blankenstein MA (2004) The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas. Mol Hum Reprod 10:589–598PubMedCrossRefGoogle Scholar
  6. 6.
    van Dijk M, Mulders J, Könst A, Janssens B, Van Roy F, Blankenstein M, Oudejans CBM (2004) Differential downregulation of alphaT-catenin expression in placenta: trophoblast cell type-dependent imprinting of the CTNNA3 gene. Gene Expr Patterns 5:61–65PubMedCrossRefGoogle Scholar
  7. 7.
    Vanpoucke G, Goossens S, De Craene B, Gilbert B, Van Roy F, Berx G (2004) GATA-4 and MEF2C transcription factors control the tissue-specific expression of the alphaT-catenin gene CTNNA3. Nucleic Acids Res 32:4155–4165PubMedCrossRefGoogle Scholar
  8. 8.
    van Dijk M, Mulders J, Poutsma A, Könst AAM, Lachmeijer AMA, Dekker GA, Blankenstein MA, Oudejans CBM (2005) Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged-helix gene family. Nat Genet 37:514–519PubMedCrossRefGoogle Scholar
  9. 9.
    van Dijk M, van Bezu J, van Abel D, Dunk C, Blankenstein MA, Oudejans CB, Lye SJ (2010) The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation. Hum Mol Genet 19:2658–2667PubMedCrossRefGoogle Scholar
  10. 10.
    Goossens S, Janssens B, Vanpoucke G, De Rycke R, van Hengel J, Van Roy F (2007) Truncated isoform of mouse alphaT-catenin is testis-restricted in expression and function. FASEB J 21:647–655PubMedCrossRefGoogle Scholar
  11. 11.
    Busby V et al (2004) Alpha-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer’s disease. Neuromolecular Med 5(2):133–146PubMedCrossRefGoogle Scholar
  12. 12.
    Smith D, Zhu Y, McAvoy S, Kuhn R (2006) Common fragile sites, extremely large genes, neural development and cancer. Cancer Lett 232:48–57PubMedCrossRefGoogle Scholar
  13. 13.
    Matthews CP, Shera K, Kiviat N, McDougall JK (2001) Expression of truncated FHIT transcripts in cervical cancers and in normal human cells. Oncogene 20:4665–4675PubMedCrossRefGoogle Scholar
  14. 14.
    Driouch K, Prydz H, Monese R, Johansen H, Lidereau R, Frengen E (2002) Alternative transcripts of the candidate tumor suppressor gene, WWOX, are expressed at high levels in human breast tumors. Oncogene 21:1832–1840PubMedCrossRefGoogle Scholar
  15. 15.
    Denison SR, Wang F, Becker NA, Schüle B, Kock N, Phillips LA, Klein C, Smith DI (2003) Alterations in the common fragile site gene Parkin in ovarian and other cancers. Oncogene 22:8370–8378PubMedCrossRefGoogle Scholar
  16. 16.
    Smith DI, McAvoy S, Zhu Y, Perez DS (2007) Large common fragile site genes and cancer. Semin Cancer Biol 17(1):31–41PubMedCrossRefGoogle Scholar
  17. 17.
    Durkin SG, Glover TW (2007) Chromosome fragile sites. Annu Rev Genet 41:169–192PubMedCrossRefGoogle Scholar
  18. 18.
    Ertekin-Taner N, Ronald J, Asahara H, Younkin L, Hella M, Jain S, Gnida E, Younkin S, Fadale D, Ohyagi Y, Singleton A, Scanlin L, de Andrade M, Petersen R, Graff-Radford N, Hutton M, Younkin S (2003) Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer’s disease pedigrees. Hum Mol Genet 12(23):3133–3143PubMedCrossRefGoogle Scholar
  19. 19.
    Blomqvist ME, Andreasen N, Bogdanovic N, Blennow K, Brookes AJ, Prince JA (2004) Genetic variation in CTNNA3 encoding alpha-3 catenin and Alzheimer’s disease. Neurosci Lett 358(3):220–222PubMedCrossRefGoogle Scholar
  20. 20.
    Martin ER, Bronson PG, Li YJ, Wall N, Chung RH, Schmechel DE, Small G, Xu PT, Bartlett J, Schnetz-Boutaud N, Haines JL, Gilbert JR, Pericak-Vance MA (2005) Interaction between the alpha-T-catenin gene (VR22) and APOE in Alzheimer’s disease. J Med Genet 42(10):787–792PubMedCrossRefGoogle Scholar
  21. 21.
    Cellini E, Bagnoli S, Tedde A, Nacmias B, Piacentini S, Sorbi S (2005) Insulin degrading enzyme and alpha-3 catenin polymorphisms in Italian patients with Alzheimer disease. Alzheimer Dis Assoc Disord 19(4):246–247PubMedCrossRefGoogle Scholar
  22. 22.
    Bertram L, Mullin K, Parkinson M, Hsiao M, Moscarillo TJ, Wagner SL, Becker KD, Velicelebi G, Blacker D, Tanzi RE (2007) Is alpha-T-catenin (VR22) an Alzheimer’s disease risk gene? J Med Genet 44(1):e63PubMedCrossRefGoogle Scholar
  23. 23.
    Miyashita A, Arai H, Asada T, Imagawa M, Matsubara E, Shoji M, Higuchi S, Urakami K, Kakita A, Takahashi H, Toyabe S, Akazawa K, Kanazawa I, Ihara Y, Kuwano R, Japanese Genetic Study Consortium for Alzeheimer’s Disease. (2007) Genetic association of CTNNA3 with late-onset Alzheimer’s disease in females. Hum Mol Genet 16(23):2854–2869PubMedCrossRefGoogle Scholar
  24. 24.
    Goossens S, Janssens B, Bonné S, De Rycke R, Braet F, van Hengel J, van Roy F (2007) A unique and specific interaction between alphaT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs. J Cell Sci 120(Pt 12):2126–2136PubMedCrossRefGoogle Scholar
  25. 25.
    Christensen AH, Benn M, Tybjærg-Hansen A, Haunso S, Svendsen JH (2011) Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy. Genet Test Mol Biomarkers 15(4):267–271PubMedCrossRefGoogle Scholar
  26. 26.
    Soldà G, Suyama M, Pelucchi P, Boi S, Guffanti A, Rizzi E, Bork P, Tenchini ML, Ciccarelli FD (2008) Non-random retention of protein-coding overlapping genes in Metazoa. BMC Genomics 9:174PubMedCrossRefGoogle Scholar
  27. 27.
    Yu P, Ma D, Xu M (2005) Nested genes in the human genome. Genomics 86:414–422PubMedCrossRefGoogle Scholar
  28. 28.
    Assis R, Kondrashov AS, Koonin EV, Kondrashov FA (2008) Nested genes and increasing organizational complexity of metazoan genomes. Trends Genet 24:475–478PubMedCrossRefGoogle Scholar
  29. 29.
    Habib AA, Gulcher JR, Högnason T, Zheng L, Stefánsson K (1998) The OMgp gene, a second growth suppressor within the NF1 gene. Oncogene 16:1525–1531PubMedCrossRefGoogle Scholar
  30. 30.
    Crampton N, Bonass WA, Kirkham J, Rivetti C, Thomson NH (2006) Collision events between RNA polymerases in convergent transcription studied by atomic force microscopy. Nucleic Acids Res 34:5416–5425PubMedCrossRefGoogle Scholar
  31. 31.
    Laurén J, Airaksinen MS, Saarma M, Timmusk T (2003) A novel gene family encoding leucine-rich repeat transmembrane proteins differentially expressed in the nervous system. Genomics 81:411–421PubMedCrossRefGoogle Scholar
  32. 32.
    Kobe B, Kajava AV (2001) The leucine-rich repeat as a protein recognition motif. Curr Opin Struct Biol 11:725–732PubMedCrossRefGoogle Scholar
  33. 33.
    Linhoff MW, Laurén J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, Airaksinen MS, Strittmatter SM, Craig AM (2009) An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 61:734–749PubMedCrossRefGoogle Scholar
  34. 34.
    Majercak J, Ray WJ, Espeseth A, Simon A, Shi XP, Wolffe C, Getty K, Marine S, Stec E, Ferrer M, Strulovici B, Bartz S, Gates A, Xu M, Huang Q, Ma L, Shughrue P, Burchard J, Colussi D, Pietrak B, Kahana J, Beher D, Rosahl T, Shearman M, Hazuda D, Sachs AB, Koblan KS, Seabrook GR, Stone DJ (2006) LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer’s disease. Proc Natl Acad Sci USA 103:17967–17972PubMedCrossRefGoogle Scholar
  35. 35.
    Brena RM, Huang TH-M, Plass C (2006) Toward a human epigenome. Nat Genet 38:1359–1360PubMedCrossRefGoogle Scholar
  36. 36.
    Suzuki M, Sato S, Arai Y, Shinohara T, Tanaka S, Greally JM, Hattori N, Shiota K (2007) A new class of tissue-specifically methylated regions involving entire CpG Islands in the mouse. Genes Cells 12:1305–1314PubMedCrossRefGoogle Scholar
  37. 37.
    Meehan M, Melvin A, Gallagher E, Smith J, McGoldrick A, Moss C, Goossens S, Harrison M, Kay E, Fitzpatrick J, Dervan P, Mc Cann A (2007) Alpha-T-catenin (CTNNA3) displays tumour-specific monoallelic expression in urothelial carcinoma of the bladder. Genes Chromosom Cancer 46:587–593PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • James D. Smith
    • 1
    • 2
  • Maria H. Meehan
    • 1
    • 2
  • John Crean
    • 1
    • 3
  • Amanda McCann
    • 1
    • 2
    Email author
  1. 1.UCD Conway Institute of Biomolecular and Biomedical ResearchUniversity College Dublin (UCD)Dublin 4Ireland
  2. 2.UCD School of Medicine and Medical Science (UCD SMMS)University College Dublin (UCD)Dublin 4Ireland
  3. 3.UCD School of Biomolecular and Biomedical Sciences (UCD SBBS)University College Dublin (UCD)Dublin 4Ireland

Personalised recommendations