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NOD2

Reviewed August 2007

What is the official name of the NOD2 gene?

The official name of this gene is “nucleotide-binding oligomerization domain containing 2.”

NOD2 is the gene's official symbol. The NOD2 gene is also known by other names, listed below.

What is the normal function of the NOD2 gene?

The NOD2 gene provides instructions for making a protein called nucleotide-binding oligomerization domain containing 2. This protein is active in some types of immune system cells (such as monocytes, macrophages, and dendritic cells), which help protect the body against foreign invaders such as viruses and bacteria. The NOD2 protein is also active in several types of epithelial cells, including Paneth cells, which are found in the lining of the intestine. These cells play an important role in defending the intestinal wall against bacterial infection.

Many types of bacteria commonly live in the digestive system. Most of them are harmless, such as bacteria in the intestine that normally help digest food. Other bacteria, however, can infect the body and cause disease. The NOD2 protein is involved in recognizing certain bacteria in the intestine and stimulating the immune system to respond properly. When triggered by specific substances produced by bacteria, the NOD2 protein activates a protein complex called nuclear factor-kappa-B. This protein complex regulates the activity of multiple genes, including genes that control immune responses and inflammatory reactions. By activating nuclear factor-kappa-B, the NOD2 protein helps protect the digestive tract from bacterial invasion.

Does the NOD2 gene share characteristics with other genes?

The NOD2 gene belongs to a family of genes called NLR (nucleotide-binding domain and leucine rich repeat containing family).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the NOD2 gene related to health conditions?

Crohn disease - increased risk from variations of the NOD2 gene

More than 30 variations in the NOD2 gene have been associated with an increased risk of Crohn disease in the lower part of the small intestine (the ileum). This increased risk has been found only in Caucasian (white) populations. The most common variation, written as 3020insC or 1007fs, leads to the production of a NOD2 protein that is slightly shorter than normal. Other common variations change single protein building blocks (amino acids) in the NOD2 protein. It is unclear how these genetic changes increase the risk of developing Crohn disease. Several studies have suggested that changes in the NOD2 gene prevent the protein from recognizing bacteria, allowing these microbes to grow unchecked and invade cells lining the intestine. An abnormal immune response to these bacteria may lead to chronic inflammation and the digestive problems characteristic of Crohn disease.

cancers - associated with the NOD2 gene

A few studies have suggested a possible association between changes in the NOD2 gene, particularly the common variation 3020insC, and the development of certain cancers. Although some of these studies found an increased risk of cancer in people with a NOD2 variation, other research found no such association.

other disorders - associated with the NOD2 gene

Mutations in the NOD2 gene have been identified in several families with a rare condition called Blau syndrome. This disorder is characterized by inflammation of the eye (uveitis), early-onset arthritis, unusual curvature of the fingers (camptodactyly), and a persistent skin rash. Researchers have found at least two NOD2 mutations in people with Blau syndrome. The identified mutations each change a single protein building block (amino acid) at position 334 in the NOD2 protein. At this position, the amino acid arginine is replaced with the amino acid glutamine (written as Arg334Gln or R334Q) or with the amino acid tryptophan (written as Arg334Trp or R334W). These mutations occur in a different region of the NOD2 gene than the genetic variations associated with an increased risk of Crohn disease.

Changes in the NOD2 gene also may be associated with early-onset sarcoidosis, a condition with signs and symptoms similar to Blau syndrome. Although NOD2 mutations have been found in a few families with early-onset sarcoidosis, researchers believe that these genetic changes are unlikely to be a major risk factor for this disorder.

Several studies have considered variations in the NOD2 gene as a possible risk factor for a condition called graft-versus-host disease (GVHD). Graft-versus-host disease can occur following certain cancer treatments, such as allogeneic stem cell transplantation. This procedure, which is typically used to treat cancers of the blood and immune system, replaces a patient's diseased blood-forming cells (a type of stem cell) with stem cells from a healthy donor. If the donor's stem cells (the graft) recognize the patient's body (the host) as foreign, they may attack organs and tissues such as the liver, digestive system, and skin. This potentially severe reaction is known as graft-versus-host disease. Researchers believe that variations in the NOD2 gene may influence the risk of developing severe complications of graft-versus-host disease following an allogeneic stem cell transplant. The presence of NOD2 variations in both the stem cell donor and the recipient is associated with the greatest risk of a severe reaction.

Where is the NOD2 gene located?

Cytogenetic Location: 16q21

Molecular Location on chromosome 16: base pairs 50,731,049 to 50,766,986

The NOD2 gene is located on the long (q) arm of chromosome 16 at position 21.

The NOD2 gene is located on the long (q) arm of chromosome 16 at position 21.

More precisely, the NOD2 gene is located from base pair 50,731,049 to base pair 50,766,986 on chromosome 16.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about NOD2?

You and your healthcare professional may find the following resources about NOD2 helpful.

  • MedlinePlus - Health information

    • Encyclopedia: Graft-Versus-Host Disease (http://www.nlm.nih.gov/medlineplus/ency/article/001309.htm)
    • Encyclopedia: Sarcoidosis (http://www.nlm.nih.gov/medlineplus/ency/article/000076.htm)

  • Gene Tests - DNA tests ordered by healthcare professionals

    • Gene Tests: Blau Syndrome (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/227309)
    • Gene Tests: Crohn Disease (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/173599)

You may also be interested in these resources, which are designed for genetics professionals and researchers.

  • PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=((CARD15%5BTIAB%5D)%20OR%20(NOD2%5BTIAB%5D))%20AND%20((Genes%5BMH%5D)%20OR%20(Genetic%20Phenomena%5BMH%5D))%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%20360%20days%22%5Bdp%5D)

  • OMIM - Genetic disorder catalog

    • BLAU SYNDROME (http://omim.org/entry/186580)
    • NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2 (http://omim.org/entry/605956)

  • Research Resources - Tools for researchers

    • Atlas of Genetics and Cytogenetics in Oncology and Haematology (http://atlasgeneticsoncology.org/Genes/GC_NOD2.html)
    • Entrez Gene (http://www.ncbi.nlm.nih.gov/gene/64127)
    • GeneCards (http://www.genecards.org/cgi-bin/carddisp.pl?id_type=entrezgene&id=64127)
    • HUGO Gene Nomenclature Committee (http://www.genenames.org/data/hgnc_data.php?hgnc_id=5331)

What other names do people use for the NOD2 gene or gene products?

  • ACUG
  • BLAU
  • CARD15
  • caspase recruitment domain family, member 15
  • caspase recruitment domain protein 15
  • CD
  • IBD1
  • inflammatory bowel disease protein 1
  • LRR-containing protein
  • NOD2B
  • NOD2_HUMAN
  • PSORAS1

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding NOD2?

acids ; allogeneic ; allogeneic stem cell transplantation ; amino acid ; arthritis ; bacteria ; camptodactyly ; cancer ; caspase ; cell ; chronic ; complication ; dendritic cell ; digestive ; digestive system ; domain ; epithelial ; gene ; genetic variation ; graft-versus-host disease ; GVHD ; ileum ; immune response ; immune system ; infection ; inflammation ; innate immunity ; intestine ; juvenile ; macrophage ; monocyte ; mutation ; nucleotide ; population ; protein ; risk factors ; sarcoidosis ; sign ; stem cells ; symptom ; syndrome ; tissue ; uveitis ; virus

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, Kuechler I, Krueger S, Schmidt HH, Lochs H. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006 Mar;55(3):342-7. Epub 2005 Jul 6. (http://www.ncbi.nlm.nih.gov/pubmed/16000642?dopt=Abstract)
  • Eckmann L, Karin M. NOD2 and Crohn's disease: loss or gain of function? Immunity. 2005 Jun;22(6):661-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15963781?dopt=Abstract)
  • Elmaagacli AH, Koldehoff M, Hindahl H, Steckel NK, Trenschel R, Peceny R, Ottinger H, Rath PM, Ross RS, Roggendorf M, Grosse-Wilde H, Beelen DW. Mutations in innate immune system NOD2/CARD 15 and TLR-4 (Thr399Ile) genes influence the risk for severe acute graft-versus-host disease in patients who underwent an allogeneic transplantation. Transplantation. 2006 Jan 27;81(2):247-54. (http://www.ncbi.nlm.nih.gov/pubmed/16436969?dopt=Abstract)
  • Entrez Gene (http://www.ncbi.nlm.nih.gov/gene/64127)
  • Gasche C, Grundtner P. Genotypes and phenotypes in Crohn's disease: do they help in clinical management? Gut. 2005 Jan;54(1):162-7. Review. Erratum in: Gut. 2005 Mar;54(3):442. (http://www.ncbi.nlm.nih.gov/pubmed/15591523?dopt=Abstract)
  • Gaya DR, Russell RK, Nimmo ER, Satsangi J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet. 2006 Apr 15;367(9518):1271-84. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16631883?dopt=Abstract)
  • Henckaerts L, Vermeire S. NOD2/CARD15 disease associations other than Crohn's disease. Inflamm Bowel Dis. 2007 Feb;13(2):235-41. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17206682?dopt=Abstract)
  • Holler E, Rogler G, Herfarth H, Brenmoehl J, Wild PJ, Hahn J, Eissner G, Schölmerich J, Andreesen R. Both donor and recipient NOD2/CARD15 mutations associate with transplant-related mortality and GvHD following allogeneic stem cell transplantation. Blood. 2004 Aug 1;104(3):889-94. Epub 2004 Apr 15. (http://www.ncbi.nlm.nih.gov/pubmed/15090455?dopt=Abstract)
  • Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, Almer S, Tysk C, O'Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel JF, Sahbatou M, Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):599-603. (http://www.ncbi.nlm.nih.gov/pubmed/11385576?dopt=Abstract)
  • Hugot JP. CARD15/NOD2 mutations in Crohn's disease. Ann N Y Acad Sci. 2006 Aug;1072:9-18. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17057186?dopt=Abstract)
  • Kanazawa N, Okafuji I, Kambe N, Nishikomori R, Nakata-Hizume M, Nagai S, Fuji A, Yuasa T, Manki A, Sakurai Y, Nakajima M, Kobayashi H, Fujiwara I, Tsutsumi H, Utani A, Nishigori C, Heike T, Nakahata T, Miyachi Y. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood. 2005 Feb 1;105(3):1195-7. Epub 2004 Sep 30. (http://www.ncbi.nlm.nih.gov/pubmed/15459013?dopt=Abstract)
  • Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Häfner R, Chamaillard M, Zouali H, Thomas G, Hugot JP. CARD15 mutations in Blau syndrome. Nat Genet. 2001 Sep;29(1):19-20. (http://www.ncbi.nlm.nih.gov/pubmed/11528384?dopt=Abstract)
  • Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):603-6. (http://www.ncbi.nlm.nih.gov/pubmed/11385577?dopt=Abstract)
  • Rogler G, Holler E. Can NOD2/CARD15 mutations predict intestinal graft-versus-host disease and aid our understanding of Crohn's disease? Nat Clin Pract Gastroenterol Hepatol. 2004 Dec;1(2):62-3. (http://www.ncbi.nlm.nih.gov/pubmed/16265048?dopt=Abstract)
  • Russell RK, Nimmo ER, Satsangi J. Molecular genetics of Crohn's disease. Curr Opin Genet Dev. 2004 Jun;14(3):264-70. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15172669?dopt=Abstract)
  • Schreiber S. Slipping the barrier: how variants in CARD15 could alter permeability of the intestinal wall and population health. Gut. 2006 Mar;55(3):308-9. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16474103?dopt=Abstract)
  • Schürmann M, Valentonyte R, Hampe J, Müller-Quernheim J, Schwinger E, Schreiber S. CARD15 gene mutations in sarcoidosis. Eur Respir J. 2003 Nov;22(5):748-54. (http://www.ncbi.nlm.nih.gov/pubmed/14621080?dopt=Abstract)
  • Vermeire S, Rutgeerts P. Current status of genetics research in inflammatory bowel disease. Genes Immun. 2005 Dec;6(8):637-45. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16107869?dopt=Abstract)
  • Wang X, Kuivaniemi H, Bonavita G, Mutkus L, Mau U, Blau E, Inohara N, Nunez G, Tromp G, Williams CJ. CARD15 mutations in familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy. Arthritis Rheum. 2002 Nov;46(11):3041-5. (http://www.ncbi.nlm.nih.gov/pubmed/12428248?dopt=Abstract)
  • Watanabe T, Kitani A, Strober W. NOD2 regulation of Toll-like receptor responses and the pathogenesis of Crohn's disease. Gut. 2005 Nov;54(11):1515-8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16227353?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: August 2007
Published: May 21, 2012