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Gene Review

NOD2  -  nucleotide-binding oligomerization domain...

Homo sapiens

Synonyms: ACUG, BLAU, CARD15, CD, CLR16.3, ...
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Disease relevance of NOD2


Psychiatry related information on NOD2


High impact information on NOD2


Chemical compound and disease context of NOD2


Biological context of NOD2


Anatomical context of NOD2


Associations of NOD2 with chemical compounds

  • Despite observed differences in TNF production in mucosal biopsy tissue, there was no relationship between the overall presence of a mutation in NOD2/CARD15 or of any of the mutations separately and short-term infliximab response or response duration [28].
  • Nod2 (CARD15) is a macrophage-specific protein containing two CARD domains, a large nucleotide binding domain and leucine-rich repeats [29].
  • IEC transfected with the Crohn-specific CARD15 mutant (F3020insC, FS) failed to activate NFkB after MDP-challenge, in contrast to CARD15WT IEC [26].
  • METHODS: In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives) [30].
  • A recently described mutation (2936insC) in CARD15 and a polymorphism in TLR4 896 A>G impair responses to LPS [27].
  • A serological dosage effect was also observed. gASCA and AMCA antibodies were associated with NOD2/CARD15, in addition to a gene-dosage effect [31].

Physical interactions of NOD2

  • The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants [32].
  • Nod2 interacted with the serine-threonine kinase RICK via a homophilic CARD-CARD interaction [33].
  • Nod2 appears to interact with TAK1 through its LRR region to exert its inhibitory effect on TAK1-induced NF-kappaB activation [34].
  • In addition, a change in the dynamics of the Erbin/Nod2 complex was observed during Shigella flexneri infection [35].
  • The recognition of peptidoglycan by cells of the innate immune system has been controversial; both TLR2 and nucleotide-binding oligomerization domain-2 (NOD2) have been implicated in this process [36].

Co-localisations of NOD2

  • CENTB1 partially co-localized with NOD2 and NOD1 proteins in the cytoplasm of mammalian cells [37].

Regulatory relationships of NOD2

  • RESULTS: TNF-alpha induced an up-regulation of NOD2 in epithelial cell lines (HT-29, SW620, SW948, HeLa S3) and in primary colonic epithelial cells [38].
  • Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease [39].
  • Together, these data suggest that NOD2 serves as an intracellular pattern recognition receptor to enhance host defense by inducing the production of antimicrobial peptides such as hBD-2 [18].
  • Suppression of the mRNA expression of nucleotide-binding oligomerization domain (NOD)1 and NOD2 by RNA interference specifically inhibited the synergistic IL-8 secretion induced by DMP and MDP with these TLR agonists respectively [40].
  • The dominant negative form of TAK1 abolished muramyl dipeptide-induced NF-kappaB activation in Nod2-expressing cells [34].
  • We also show that NOD2 promotes the membrane recruitment of RICK, a serine-threonine kinase involved in NF-kappaB activation downstream of NOD2 [41].

Other interactions of NOD2

  • A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033) [3].
  • Multipoint non-parametric linkage analyses were performed, with further stratification of affection status by common CARD15 mutations and the IBD5 haplotype [32].
  • Evidence for linkage to chromosome 19 (IBD6) was observed in Crohn's disease pairs not possessing CARD15 mutations (P=0.0001), and in pairs possessing one or two copies of the IBD5 risk haplotype (P=0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively [32].
  • Because CARD4/NOD1 shares many structural and functional similarities with CARD15, we tested its putative role in IBD [42].
  • We did not find a significant correlation between granulomas and TLR4 or CARD15 variants [43].

Analytical, diagnostic and therapeutic context of NOD2


  1. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Peltekova, V.D., Wintle, R.F., Rubin, L.A., Amos, C.I., Huang, Q., Gu, X., Newman, B., Van Oene, M., Cescon, D., Greenberg, G., Griffiths, A.M., St George-Hyslop, P.H., Siminovitch, K.A. Nat. Genet. (2004) [Pubmed]
  2. A risk haplotype in the Solute Carrier Family 22A4/22A5 gene cluster influences phenotypic expression of Crohn's disease. Newman, B., Gu, X., Wintle, R., Cescon, D., Yazdanpanah, M., Liu, X., Peltekova, V., Van Oene, M., Amos, C.I., Siminovitch, K.A. Gastroenterology (2005) [Pubmed]
  3. Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD. Vermeire, S., Pierik, M., Hlavaty, T., Claessens, G., van Schuerbeeck, N., Joossens, S., Ferrante, M., Henckaerts, L., Bueno de Mesquita, M., Vlietinck, R., Rutgeerts, P. Gastroenterology (2005) [Pubmed]
  4. Evidence for common genetic control in pathways of inflammation for Crohn's disease and psoriatic arthritis. Ho, P., Bruce, I.N., Silman, A., Symmons, D., Newman, B., Young, H., Griffiths, C.E., John, S., Worthington, J., Barton, A. Arthritis Rheum. (2005) [Pubmed]
  5. NOD2 variants and antibody response to microbial antigens in Crohn's disease patients and their unaffected relatives. Devlin, S.M., Yang, H., Ippoliti, A., Taylor, K.D., Landers, C.J., Su, X., Abreu, M.T., Papadakis, K.A., Vasiliauskas, E.A., Melmed, G.Y., Fleshner, P.R., Mei, L., Rotter, J.I., Targan, S.R. Gastroenterology (2007) [Pubmed]
  6. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Aróstegui, J.I., Arnal, C., Merino, R., Modesto, C., Antonia Carballo, M., Moreno, P., García-Consuegra, J., Naranjo, A., Ramos, E., de Paz, P., Rius, J., Plaza, S., Yagüe, J. Arthritis Rheum. (2007) [Pubmed]
  7. Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis. Okafuji, I., Nishikomori, R., Kanazawa, N., Kambe, N., Fujisawa, A., Yamazaki, S., Saito, M., Yoshioka, T., Kawai, T., Sakai, H., Tanizaki, H., Heike, T., Miyachi, Y., Nakahata, T. Arthritis Rheum. (2009) [Pubmed]
  8. Use of azathioprine or 6-mercaptopurine in the treatment of Crohn's disease. O'Brien, J.J., Bayless, T.M., Bayless, J.A. Gastroenterology (1991) [Pubmed]
  9. Inflammatory bowel disease in children and adolescents: mental health and family functioning. Engstrom, I. J. Pediatr. Gastroenterol. Nutr. (1999) [Pubmed]
  10. Social learning, affective state and passive coping in irritable bowel syndrome and inflammatory bowel disease. Crane, C., Martin, M. General hospital psychiatry. (2004) [Pubmed]
  11. Gastrointestinal and nutritional aspects of eating disorders. McClain, C.J., Humphries, L.L., Hill, K.K., Nickl, N.J. Journal of the American College of Nutrition. (1993) [Pubmed]
  12. The influence of personality factors on health-related quality of life of patients with inflammatory bowel disease. Moreno-Jim??nez, B., L??pez Blanco, B., Rodr??guez-Mu??oz, A., Garrosa Hern??ndez, E. Journal of psychosomatic research (2007) [Pubmed]
  13. Genetic variation in DLG5 is associated with inflammatory bowel disease. Stoll, M., Corneliussen, B., Costello, C.M., Waetzig, G.H., Mellgard, B., Koch, W.A., Rosenstiel, P., Albrecht, M., Croucher, P.J., Seegert, D., Nikolaus, S., Hampe, J., Lengauer, T., Pierrou, S., Foelsch, U.R., Mathew, C.G., Lagerstrom-Fermer, M., Schreiber, S. Nat. Genet. (2004) [Pubmed]
  14. CARD15 mutations in Blau syndrome. Miceli-Richard, C., Lesage, S., Rybojad, M., Prieur, A.M., Manouvrier-Hanu, S., Häfner, R., Chamaillard, M., Zouali, H., Thomas, G., Hugot, J.P. Nat. Genet. (2001) [Pubmed]
  15. Inflammatory bowel disease, psoriasis, and complement. Rosenberg, E.W., Spitzer, R.E., Marley, W.M., Belew, P.W. N. Engl. J. Med. (1982) [Pubmed]
  16. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Ogura, Y., Bonen, D.K., Inohara, N., Nicolae, D.L., Chen, F.F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R.H., Achkar, J.P., Brant, S.R., Bayless, T.M., Kirschner, B.S., Hanauer, S.B., Nuñez, G., Cho, J.H. Nature (2001) [Pubmed]
  17. Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection. Rosenstiel, P., Hellmig, S., Hampe, J., Ott, S., Till, A., Fischbach, W., Sahly, H., Lucius, R., Fölsch, U.R., Philpott, D., Schreiber, S. Cell. Microbiol. (2006) [Pubmed]
  18. NOD2/CARD15 mediates induction of the antimicrobial peptide human beta-defensin-2. Voss, E., Wehkamp, J., Wehkamp, K., Stange, E.F., Schröder, J.M., Harder, J. J. Biol. Chem. (2006) [Pubmed]
  19. Relationship between clinical features of Crohn's disease and the risk of developing extraintestinal manifestations. Barreiro-de Acosta, M., Enrique Dom??nguez-Mu??oz, J., Concepcion N????ez-Pardo de Vera, M., Lozano-Le??n, A., Lorenzo, A., Pe??a, S. European journal of gastroenterology & hepatology (2007) [Pubmed]
  20. Crohn's disease and the NOD2 gene: a role for paneth cells. Lala, S., Ogura, Y., Osborne, C., Hor, S.Y., Bromfield, A., Davies, S., Ogunbiyi, O., Nuñez, G., Keshav, S. Gastroenterology (2003) [Pubmed]
  21. Inflammatory bowel disease associated with levamisole and fluorouracil chemotherapy for colon cancer. Atkins, C.D. J. Natl. Cancer Inst. (1996) [Pubmed]
  22. The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease. Noble, C.L., Nimmo, E.R., Drummond, H., Ho, G.T., Tenesa, A., Smith, L., Anderson, N., Arnott, I.D., Satsangi, J. Gastroenterology (2005) [Pubmed]
  23. CARD15 genetic variation in a Quebec population: prevalence, genotype-phenotype relationship, and haplotype structure. Vermeire, S., Wild, G., Kocher, K., Cousineau, J., Dufresne, L., Bitton, A., Langelier, D., Pare, P., Lapointe, G., Cohen, A., Daly, M.J., Rioux, J.D. Am. J. Hum. Genet. (2002) [Pubmed]
  24. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. McGovern, D.P., Hysi, P., Ahmad, T., van Heel, D.A., Moffatt, M.F., Carey, A., Cookson, W.O., Jewell, D.P. Hum. Mol. Genet. (2005) [Pubmed]
  25. Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. Opitz, B., Püschel, A., Schmeck, B., Hocke, A.C., Rosseau, S., Hammerschmidt, S., Schumann, R.R., Suttorp, N., Hippenstiel, S. J. Biol. Chem. (2004) [Pubmed]
  26. Microbial induction of CARD15 expression in intestinal epithelial cells via toll-like receptor 5 triggers an antibacterial response loop. Begue, B., Dumant, C., Bambou, J.C., Beaulieu, J.F., Chamaillard, M., Hugot, J.P., Goulet, O., Schmitz, J., Philpott, D.J., Cerf-Bensussan, N., Ruemmele, F.M. J. Cell. Physiol. (2006) [Pubmed]
  27. The CARD15 2936insC mutation and TLR4 896 A>G polymorphism in African Americans and risk of preterm premature rupture of membranes (PPROM). Ferrand, P.E., Fujimoto, T., Chennathukuzhi, V., Parry, S., Macones, G.A., Sammel, M., Kuivaniemi, H., Romero, R., Strauss, J.F. Mol. Hum. Reprod. (2002) [Pubmed]
  28. NOD2/CARD15 does not influence response to infliximab in Crohn's disease. Vermeire, S., Louis, E., Rutgeerts, P., De Vos, M., Van Gossum, A., Belaiche, J., Pescatore, P., Fiasse, R., Pelckmans, P., Vlietinck, R., Merlin, F., Zouali, H., Thomas, G., Colombel, J.F., Hugot, J.P. Gastroenterology (2002) [Pubmed]
  29. Role of nod2 in the response of macrophages to toll-like receptor agonists. Pauleau, A.L., Murray, P.J. Mol. Cell. Biol. (2003) [Pubmed]
  30. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy. Fries, W., Renda, M.C., Lo Presti, M.A., Raso, A., Orlando, A., Oliva, L., Giofré, M.R., Maggio, A., Mattaliano, A., Macaluso, A., Cottone, M. Am. J. Gastroenterol. (2005) [Pubmed]
  31. New serological markers for inflammatory bowel disease are associated with earlier age at onset, complicated disease behavior, risk for surgery, and NOD2/CARD15 genotype in a Hungarian IBD cohort. Papp, M., Altorjay, I., Dotan, N., Palatka, K., Foldi, I., Tumpek, J., Sipka, S., Udvardy, M., Dinya, T., Lakatos, L., Kovacs, A., Molnar, T., Tulassay, Z., Miheller, P., Norman, G.L., Szamosi, T., Papp, J., Lakatos, P.L. Am. J. Gastroenterol. (2008) [Pubmed]
  32. The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants. van Heel, D.A., Dechairo, B.M., Dawson, G., McGovern, D.P., Negoro, K., Carey, A.H., Cardon, L.R., Mackay, I., Jewell, D.P., Lench, N.J. Hum. Mol. Genet. (2003) [Pubmed]
  33. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. Ogura, Y., Inohara, N., Benito, A., Chen, F.F., Yamaoka, S., Nunez, G. J. Biol. Chem. (2001) [Pubmed]
  34. Reciprocal cross-talk between Nod2 and TAK1 signaling pathways. Chen, C.M., Gong, Y., Zhang, M., Chen, J.J. J. Biol. Chem. (2004) [Pubmed]
  35. Role for erbin in bacterial activation of Nod2. Kufer, T.A., Kremmer, E., Banks, D.J., Philpott, D.J. Infect. Immun. (2006) [Pubmed]
  36. Nucleotide-binding oligomerization domain-2 modulates specific TLR pathways for the induction of cytokine release. Netea, M.G., Ferwerda, G., de Jong, D.J., Jansen, T., Jacobs, L., Kramer, M., Naber, T.H., Drenth, J.P., Girardin, S.E., Kullberg, B.J., Adema, G.J., Van der Meer, J.W. J. Immunol. (2005) [Pubmed]
  37. Centaurin beta1 Down-regulates Nucleotide-binding Oligomerization Domains 1- and 2-dependent NF-{kappa}B Activation. Yamamoto-Furusho, J.K., Barnich, N., Xavier, R., Hisamatsu, T., Podolsky, D.K. J. Biol. Chem. (2006) [Pubmed]
  38. TNF-alpha and IFN-gamma regulate the expression of the NOD2 (CARD15) gene in human intestinal epithelial cells. Rosenstiel, P., Fantini, M., Bräutigam, K., Kühbacher, T., Waetzig, G.H., Seegert, D., Schreiber, S. Gastroenterology (2003) [Pubmed]
  39. Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease. van Heel, D.A., Hunt, K.A., Ghosh, S., Hervé, M., Playford, R.J. Eur. J. Immunol. (2006) [Pubmed]
  40. Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. Uehara, A., Yang, S., Fujimoto, Y., Fukase, K., Kusumoto, S., Shibata, K., Sugawara, S., Takada, H. Cell. Microbiol. (2005) [Pubmed]
  41. The NOD2-RICK complex signals from the plasma membrane. Lécine, P., Esmiol, S., Métais, J.Y., Nicoletti, C., Nourry, C., McDonald, C., Nunez, G., Hugot, J.P., Borg, J.P., Ollendorff, V. J. Biol. Chem. (2007) [Pubmed]
  42. CARD4/NOD1 is not involved in inflammatory bowel disease. Zouali, H., Lesage, S., Merlin, F., Cézard, J.P., Colombel, J.F., Belaiche, J., Almer, S., Tysk, C., O'Morain, C., Gassull, M., Christensen, S., Finkel, Y., Modigliani, R., Gower-Rousseau, C., Macry, J., Chamaillard, M., Thomas, G., Hugot, J.P. Gut (2003) [Pubmed]
  43. Epithelioid granulomas, pattern recognition receptors, and phenotypes of Crohn's disease. Pierik, M., De Hertogh, G., Vermeire, S., Van Assche, G., Van Eyken, P., Joossens, S., Claessens, G., Vlietinck, R., Rutgeerts, P., Geboes, K. Gut (2005) [Pubmed]
  44. Genetic and environmental factors in monozygotic twins with Crohn's disease and their first-degree relatives: a case report. Vind, I., Jespersgaard, C., Hougs, L., Riis, L., Dinesen, L., Andersen, P.S., Locht, H., Jess, T., Munkholm, P. Digestion (2005) [Pubmed]
  45. Recent advances in the genetics of inflammatory bowel disease. Newman, B., Siminovitch, K.A. Current opinion in gastroenterology. (2005) [Pubmed]
  46. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: phenotype-genotype correlations. Lakatos, P.L., Lakatos, L., Szalay, F., Willheim-Polli, C., Osterreicher, C., Tulassay, Z., Molnar, T., Reinisch, W., Papp, J., Mozsik, G., Ferenci, P. World J. Gastroenterol. (2005) [Pubmed]
  47. Implication of TNF-related apoptosis-inducing ligand in inflammatory intestinal epithelial lesions. Begue, B., Wajant, H., Bambou, J.C., Dubuquoy, L., Siegmund, D., Beaulieu, J.F., Canioni, D., Berrebi, D., Brousse, N., Desreumaux, P., Schmitz, J., Lentze, M.J., Goulet, O., Cerf-Bensussan, N., Ruemmele, F.M. Gastroenterology (2006) [Pubmed]
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