Abstract
Some genes involved in complex human diseases are particularly vulnerable to genetic variations such as single nucleotide polymorphism, copy number variations, and mutations. For example, Ras mutations account for over 30 % of all human cancers. Additionally, there are some genes that can display different variations with functional impact in different diseases that are unrelated. One such gene stands out: δ-catenin/NPRAP/Neurojungin with gene designation as CTNND2 on chromosome 5p15.2. Recent advances in genome wide association as well as molecular biology approaches have uncovered striking involvement of δ-catenin gene variations linked to complex human disorders. These disorders include cancer, bipolar disorder, schizophrenia, autism, Cri-du-chat syndrome, myopia, cortical cataract-linked Alzheimer’s disease, and infectious diseases. This list has rapidly grown longer in recent years, underscoring the pivotal roles of δ-catenin in critical human diseases. δ-Catenin is an adhesive junction-associated protein in the delta subfamily of the β-catenin superfamily. δ-Catenin functions in Wnt signaling to regulate gene expression and modulate Rho GTPases of the Ras superfamily in cytoskeletal reorganization. δ-Catenin likely lies where Wnt signaling meets Rho GTPases and is a unique and vulnerable common target for mutagenesis in different human diseases.
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Arikkath J, Peng I-FF, Ng YG et al (2009) Delta-catenin regulates spine and synapse morphogenesis and function in hippocampal neurons during development. J Neurosci 29:5435–5442. doi:10.1523/JNEUROSCI.0835-09.2009
Atkinson A, Garnier S, Afridi S et al (2012) Genetic variations in genes involved in heparan sulphate biosynthesis are associated with Plasmodium falciparum parasitaemia: a familial study in Burkina Faso. Malar J 11:108. doi:10.1186/1475-2875-11-108
Band G, Le QS, Jostins L et al (2013) Imputation-based meta-analysis of severe malaria in three African populations. PLoS Genet 9:e1003509. doi:10.1371/journal.pgen.1003509
Bareiss S, Kim K, Lu Q (2010) Delta-catenin/NPRAP: a new member of the glycogen synthase kinase-3beta signaling complex that promotes beta-catenin turnover in neurons. J Neurosci Res 88:2350–2363. doi:10.1002/jnr.22414
Belcaro C, Dipresa S, Morini G et al (2015) CTNND2 deletion and intellectual disability. Gene 565:146–149. doi:10.1016/j.gene.2015.03.054
Brigidi GS, Sun Y, Beccano-Kelly D et al (2014) Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity. Nat Neurosci 17:522–532. doi:10.1038/nn.3657
Brown J, Bothma H, Veale R, Willem P (2011) Genomic imbalances in esophageal carcinoma cell lines involve Wnt pathway genes. World J Gastroenterol 17:2909–2923. doi:10.3748/wjg.v17.i24.2909
Burger MJ, Tebay MA, Keith PA et al (2002) Expression analysis of delta-catenin and prostate-specific membrane antigen: their potential as diagnostic markers for prostate cancer. Int J Cancer 100:228–237. doi:10.1002/ijc.10468
Guerreiro R, Hardy J (2014) Genetics of Alzheimer’s disease. Neurotherapeutics 11:732–737. doi:10.1007/s13311-014-0295-9
He Y, Kim H, Ryu T et al (2014) C-Src-mediated phosphorylation of δ-catenin increases its protein stability and the ability of inducing nuclear distribution of β-catenin. Biochim Biophys Acta 1843:758–768. doi:10.1016/j.bbamcr.2013.12.021
Herrup K (2010) Reimagining Alzheimer’s disease–an age-based hypothesis. J Neurosci 30:16755–16762. doi:10.1523/JNEUROSCI.4521-10.2010
Ho C, Zhou J, Medina M et al (2000) delta-Catenin is a nervous system-specific adherens junction protein which undergoes dynamic relocalization during development. J Comp Neurol 420:261–276
Hofmeister W, Nilsson D, Topa A et al (2015) CTNND2-a candidate gene for reading problems and mild intellectual disability. J Med Genet 52:111–122. doi:10.1136/jmedgenet-2014-102757
Huang FY, Chiu PM, Tam KF et al (2006) Semi-quantitative fluorescent PCR analysis identifies PRKAA1 on chromosome 5 as a potential candidate cancer gene of cervical cancer. Gynecol Oncol 103:219–225. doi:10.1016/j.ygyno.2006.02.028
Ide N, Hata Y, Deguchi M et al (1999) Interaction of S-SCAM with neural plakophilin-related Armadillo-repeat protein/delta-catenin. Biochem Biophys Res Commun 256:456–461. doi:10.1006/bbrc.1999.0364
Israely I, Costa RM, Xie CW et al (2004) Deletion of the neuron-specific protein delta-catenin leads to severe cognitive and synaptic dysfunction. Curr Biol 14:1657–1663. doi:10.1016/j.cub.2004.08.065
Jones SB, Lanford GW, Chen Y-H et al (2002) Glutamate-induced delta-catenin redistribution and dissociation from postsynaptic receptor complexes. Neuroscience 115:1009–1021
Jun G, Moncaster JA, Koutras C et al (2012) δ-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes. PLoS One 7:e43728. doi:10.1371/journal.pone.0043728
Kim K, Sirota A, Chen YH et al (2002) Dendrite-like process formation and cytoskeletal remodeling regulated by delta-catenin expression. Exp Cell Res 275:171–184. doi:10.1006/excr.2002.5503
Kim H, Han J-RR, Park J et al (2008a) Delta-catenin-induced dendritic morphogenesis. An essential role of p190RhoGEF interaction through Akt1-mediated phosphorylation. J Biol Chem 283:977–987. doi:10.1074/jbc.M707158200
Kim H, Oh M, Lu Q, Kim K (2008b) E-Cadherin negatively modulates delta-catenin-induced morphological changes and RhoA activity reduction by competing with p190RhoGEF for delta-catenin. Biochem Biophys Res Commun 377:636–641. doi:10.1016/j.bbrc.2008.10.030
Kim H, He Y, Yang I et al (2012) δ-Catenin promotes E-cadherin processing and activates β-catenin-mediated signaling: implications on human prostate cancer progression. Biochim Biophys Acta 1822:509–521. doi:10.1016/j.bbadis.2011.12.015
Lam CY, Tam PO, Fan DS et al (2008) A genome-wide scan maps a novel high myopia locus to 5p15. Invest Ophthalmol Vis Sci 49:3768–3778. doi:10.1167/iovs.07-1126
Liu J, Zhang HX (2014) Polymorphism in the 11q24.1 genomic region is associated with myopia: a comprehensive genetic study in Chinese and Japanese populations. Mol Vis 20:352–358
Lu Q (2010) δ-Catenin dysregulation in cancer: interactions with E-cadherin and beyond. J Pathol 222:119–123. doi:10.1002/path.2755
Lu Q, Paredes M, Medina M et al (1999) delta-catenin, an adhesive junction-associated protein which promotes cell scattering. J Cell Biol 144:519–532
Lu Q, Dobbs LJ, Gregory CW, Lanford GW, Revelo MP, Shappell S, Chen YH (2005) Increased expression of delta-catenin/neural plakophilin-related armadillo protein is associated with the down-regulation and redistribution of E-cadherin and p120ctn in human prostate cancer. Hum Pathol 36(10):1037–1048
Lu Q, Zhang J, Allison R, Gay H, Yang WX, Bhowmick NA, Frelix G, Shappell S, Chen YH (2009) Identification of extracellular delta-catenin accumulation for prostate cancer detection. Prostate 69(4):411–418
Lu B, Jiang D, Wang P et al (2011) Replication study supports CTNND2 as a susceptibility gene for high myopia. Invest Ophthalmol Vis Sci 52:8258–8261. doi:10.1167/iovs.11-7914
Mackinnon MJ, Ndila C, Uyoga S et al (2016) environmental correlation analysis for genes associated with protection against malaria. Mol Biol Evol. doi:10.1093/molbev/msw004
Matter C, Pribadi M, Liu X, Trachtenberg JT (2009) Delta-catenin is required for the maintenance of neural structure and function in mature cortex in vivo. Neuron 64:320–327. doi:10.1016/j.neuron.2009.09.026
Medina M, Marinescu RC, Overhauser J, Kosik KS (2000) Hemizygosity of delta-catenin (CTNND2) is associated with severe mental retardation in cri-du-chat syndrome. Genomics 63:157–164. doi:10.1006/geno.1999.6090
Nivard MG, Mbarek H, Hottenga JJ et al (2014) Further confirmation of the association between anxiety and CTNND2: replication in humans. Genes Brain Behav 13:195–201. doi:10.1111/gbb.12095
Nopparat J, Zhang J, Lu J-PP et al (2015) δ-Catenin, a Wnt/β-catenin modulator, reveals inducible mutagenesis promoting cancer cell survival adaptation and metabolic reprogramming. Oncogene 34:1542–1552. doi:10.1038/onc.2014.89
Oh M, Kim H, Yang I et al (2009) GSK-3 phosphorylates delta-catenin and negatively regulates its stability via ubiquitination/proteosome-mediated proteolysis. J Biol Chem 284:28579–28589. doi:10.1074/jbc.M109.002659
Paffenholz R, Franke WW (1997) Identification and localization of a neurally expressed member of the plakoglobin/armadillo multigene family. Differentiation 61:293–304. doi:10.1046/j.1432-0436.1997.6150293.x
Paffenholz R, Kuhn C, Grund C et al (1999) The arm-repeat protein NPRAP (neurojungin) is a constituent of the plaques of the outer limiting zone in the retina, defining a novel type of adhering junction. Exp Cell Res 250:452–464. doi:10.1006/excr.1999.4534
Reynolds AB (2007) p120-catenin: past and present. Biochim Biophys Acta 1773:2–7. doi:10.1016/j.bbamcr.2006.09.019
Reynolds AB, Roczniak-Ferguson A (2004) Emerging roles for p120-catenin in cell adhesion and cancer. Oncogene 23:7947–7956. doi:10.1038/sj.onc.1208161
Reynolds AB, Roesel DJ, Kanner SB, Parsons JT (1989) Transformation-specific tyrosine phosphorylation of a novel cellular protein in chicken cells expressing oncogenic variants of the avian cellular src gene. Mol Cell Biol 9:629–638
Reynolds AB, Herbert L, Cleveland JL et al (1992) p120, a novel substrate of protein tyrosine kinase receptors and of p60v-src, is related to cadherin-binding factors beta-catenin, plakoglobin and armadillo. Oncogene 7:2439–2445
Rhoads AR, Karkera JD, Detera-Wadleigh SD (1999) Radiation hybrid mapping of genes in the lithium-sensitive wnt signaling pathway. Mol Psychiatry 4:437–442
Ridge PG, Ebbert MT, Kauwe JS (2013) Genetics of Alzheimer’s disease. Biomed Res Int 2013:254954. doi:10.1155/2013/254954
Sardina JM, Walters AR, Singh KE et al (2014) Amelioration of the typical cognitive phenotype in a patient with the 5pter deletion associated with Cri-du-chat syndrome in addition to a partial duplication of CTNND2. Am J Med Genet A 164A:1761–1764. doi:10.1002/ajmg.a.36494
Schieve LA, Rice C, Yeargin-Allsopp M et al (2012) Parent-reported prevalence of autism spectrum disorders in US-born children: an assessment of changes within birth cohorts from the 2003 to the 2007 National Survey of Children’s Health. Matern Child Health J 16(Suppl 1):S151–S157. doi:10.1007/s10995-012-1004-0
Schlessinger K, Hall A, Tolwinski N (2009) Wnt signaling pathways meet Rho GTPases. Genes Dev 23:265–277. doi:10.1101/gad.1760809
Silverman JB, Restituito S, Lu W et al (2007) Synaptic anchorage of AMPA receptors by cadherins through neural plakophilin-related arm protein AMPA receptor-binding protein complexes. J Neurosci 27:8505–8516. doi:10.1523/JNEUROSCI.1395-07.2007
Sklar P, Stone JL, O’Donovan MC et al (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455:237–241. doi:10.1038/nature07239
Stefansson H, Rujescu D, Cichon S et al (2008) Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236. doi:10.1038/nature07229
Turner TN, Sharma K, Oh EC et al (2015) Loss of δ-catenin function in severe autism. Nature 520:51–56. doi:10.1038/nature14186
Vogelstein B, Papadopoulos N, Velculescu VE et al (2013) Cancer genome landscapes. Science 339:1546–1558. doi:10.1126/science.1235122
Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I et al (2008) Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Am J Hum Genet 83:504–510. doi:10.1016/j.ajhg.2008.09.011
Wang T, Chen Y-HH, Hong H et al (2009) Increased nucleotide polymorphic changes in the 5′-untranslated region of delta-catenin (CTNND2) gene in prostate cancer. Oncogene 28:555–564. doi:10.1038/onc.2008.399
Wang H, Yang M, Su S et al (2014) Association of ZNF644, GRM6 and CTNND2 genes polymorphisms with high myopia. Zhonghua Yi Xue Za Zhi 94:1289–1293
Weiss LA, Arking DE, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:802–808. doi:10.1038/nature08490
Yoo H (2015) Genetics of autism spectrum disorder: current status and possible clinical applications. Exp Neurobiol 24:257–272. doi:10.5607/en.2015.24.4.257
Yu Z, Zhou J, Chen X et al (2012) Polymorphisms in the CTNND2 gene and 11q24.1 genomic region are associated with pathological myopia in a Chinese population. Ophthalmologica 228:123–129. doi:10.1159/000338188
Yuan L, Seong E, Beuscher JL, Arikkath J (2015) δ-Catenin regulates spine architecture via cadherin and PDZ-dependent interactions. J Biol Chem 290:10947–10957. doi:10.1074/jbc.M114.632679
Zheng M, Simon R, Mirlacher M et al (2004) TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Am J Pathol 165:63–69. doi:10.1016/S0002-9440(10)63275-0
Zhou J, Liyanage U, Medina M et al (1997) Presenilin 1 interaction in the brain with a novel member of the Armadillo family. NeuroReport 8:2085–2090
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The authors wish to acknowledge the funding from US National Institutes of Health CA111891 (Q. Lu), CA165202 (Q. Lu), HL085752 (Y. H. C), ES016888 (Y. H. C), Department of Defense PC040569 (Q. Lu), Alzheimer’s North Carolina (Q. Lu) and The Wooten Foundation.
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Lu, Q., Aguilar, B.J., Li, M. et al. Genetic alterations of δ-catenin/NPRAP/Neurojungin (CTNND2): functional implications in complex human diseases. Hum Genet 135, 1107–1116 (2016). https://doi.org/10.1007/s00439-016-1705-3
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DOI: https://doi.org/10.1007/s00439-016-1705-3