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Nod2 / Card15 Gene

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NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 2; NOD2/CARD15

The NOD2 gene, short for Nucleotide-binding Oligomerization Domain containing protein 2, also known a CARD15, or Caspase Recruitment Domain Containing Protein 15, or Inflammatory Bowel Disease protein 1 (IBD1 Gene), is located on chromosome 16.

Mutations of the the NOD2/CARD15 gene is correlated with Crohn's Disease, a type of Inflammatory Bowel Disease (IBD). While Crohn's disease can be caused by multiple factors, the NOD2/CARD15 mutation can be associated with greater severity of the disease.

The NOD2/CARD15 gene may carry different mutations along the length of the gene. The location and type of mutation is associated with differing severity as well. Patients may also carry more than one mutation of the NOD2/CARD15 gene.

NOD2 / CARD15 Has An Important Role in Immune System Function

Viral Infection
- NOD2 / CARD15 activates interferon beta (IFN-beta) in response to viral infection. [3]
Bacterial Infection
- NOD2 / CARD15 activates Nuclear Factor kappa B (NF-kB) in response to bacterial infection, specifically after recognition of the bacterial cell wall component, muramyl dipeptide (MDP).[4]

- NF-kB enters the cell's nucleus and acts as a Transcription Factor for multiple Inflammatory proteins including Tumor Necrosis Factor (TNF) and Interleukin 1-beta (IL-1B).

NOD2 / CARD15 in Crohn's Disease

- Certain known mutations in the NOD2 / CARD15 gene exhibit higher liklihood of getting Crohn's Disease. NOD2 / CARD15 gene mutation is by no means a guarantee one will get Crohn's Disease.

- Crohn's disease in these patients is often of ileal location.
---- Heterozygous carriers (one copy of the mutated gene) of NOD2 / CARD15 mutations have a 2-4 -Fold Greater risk of Crohn's Disease (Ileal Location)
---- Homozygous carriers (both copies the gene are mutated) of NOD2 / CARD15 mutations have a 20-40 -Fold Greater risk of Crohn's Disease (Ileal Location)[14][15][16]

- Although not completely understood, the NOD2 / CARD15 mutations are thought to cause an ineffective feedback loop normally induced after Inflammation occurs. This feed-back loop serves to dampen the pro-inflammatory immune response.[5]

- Certain NOD2 / CARD15 mutations are associated with early onset of symptoms and prognostic course of the disease.

- The NOD2 / CARD15 mutation typically correlates with a more severe phenotype of Crohn's Disease, including Intestinal Obstruction, Strictures, and Penetration / Fistula, increasing the probability of needing surgery.

- NOD2 / CARD15 mutation is associated with ileal Crohn's Disease location.

How do NOD2/CARD15 Mutations Cause Increased NFkB Activation?

- Mutations in NOD2/CARD15 result in reduced signaling in response to microbial infection and decreased NFkB activation. However, NOD2/CARD15 is a feedback inhibitor of the Toll-Like Receptor 2 (TLR-2) pathway which activates NFkB.

- NOD2/CARD15 mutations decrease the efficacy of the feedback inhibitory pathway on NFkB, leading to the overactivation of NFkB and pro-inflammatory symptoms seen in Crohn's Disease.

NOD2 / CARD15 Genetic Testing

Genetic testing services for NOD2 / CARD15 gene mutations can be accessed here: Prometheus NOD2 / CARD15 Test

Extra-Intestinal Symptoms

- NOD2 / CARD15 mutation is associated with non-Crohn's Disease sysmptoms as well, including:

1. Uveitis - Inflammation of the eye.

2. Spondyloarthropathy - Inflammation of the vertebrae of the spinal column.

3. Early Onset Sarcoidosis (EOS) - EOS results in inflammation in multiple organ systems. Lung tissue is most often affected. Also affected can be the eye, skin, lymph nodes, liver, heart, and nervous and musculosketal systems.

Sarcoidosis typically becomes symptomatic in late childhood, however in the Early-Onset Sarcoidosis Disease form, young children are affected, usually before the age of 4.

Early Onset Sarcoidosis can be severe than Sarcoidosis that presents later in life, and can result in significant disease, blindness, and even death.

When viewed by microscopy, inflamed tissue from EOS patients exhibit nonencaseating (non-necrotic) epitheloid granulomas. These are areas of inflammation that have clusters of granuloma-type of immune cells within a circular area. The central area of these granulomas are not necrotic (dead).

4. Blau Syndrome- Blau Syndrome (BS) is correlated with NOD2 / CARD15 mutation and symptoms can be similar as those seen as in other Granulomatous diseases.

Symptoms of Blau Syndrome include:
- Granulomatous arthritis and Granulomatous skin lesions.

- Camptodactyly - is a "flexion deformity" of the fingers in which the finger is not able to fully extend. Typically seen in the little finger and is more often found in females than in males.

- A percentage of persons with Blau Syndrome also have Crohn's Disease.

NOD2 / CARD15 - Related Cancer

The NOD2 / CARD mutations have been associated with a higher incidence of specific types of cancer in affected patients. These include:

1. Crohn's disease patients with the NOD2 / CARD15 mutation have a higher likelihood of developing colorectal cancer.

2. NOD2 / CARD mutations are correlated with breast and lung cancer.

3. H. pylori - associated gastric lymphoma (H. pylori - related stomach cancer) is associated with NOD2 / CARD15 mutation.
- Recent research has shown that dietary Folic Acid (Folate), for more information, also see [12]) may help reduce this cancer risk by protecting against H. pylori- induced DNA changes (H. pylori- induced DNA demethylation) typical of precancerous and cancerous cell changes. Folic Acid or Folate may also protect against cell cancerous changes by limiting Inflammation.[11]

4. Rates of Non-Hodgkin Lymphoma (NHL) increase with NOD2 / CARD15 mutation as well.

References

1. Shurmann M, Valentonyte R, Hampe J, et al. CARD15 gene mutations in sarcoidosis. Eur Respir J. 2003;22:748-754.http://erj.ersjournals.com/content/2....full.pdf+html.

2. Orthopedic Care Center Hand and Orthopedic Upper Extremity Program, Children's Hospital Boston, MA .

3. Sabbah A, Chang TH, Harnack R, Frohlich V, Dube PH, Tominaga K, Xiang Y, & Bose S. Activation of innate immune antiviral response by NOD2. Nat. Immunol. 2009;10(10):1073-1080. http://www.ncbi.nlm.nih.gov/pmc/arti...ihms132748.pdf

4. Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NoD2: Implications for Crohn's disease. J Biol Chem. 2003;278(8):5509-5512. http://www.jbc.org/content/278/8/5509.full.pdf

5. Strober W, Kitani A, Fuss I, et al. The molecular basis of NOD2 susceptibility mutations in Crohn's disease. Mucosal Immunology. 2008;1:S5-S9. http://www.nature.com/mi/journal/v1/.../mi200842a.pdf

6. Kanazawa n, Okafuji I Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-κB activation: common genetic etiology with Blau syndrome. Blood. 2005;105(3):1195-1197. http://bloodjournal.hematologylibrar....full.pdf+html

7. Belfer MH and Stevens RW. Sarcoidosis: A Primary Care Review.Am. Fam. Physician. 1998;58(9):2041-2050. http://www.aafp.org/afp/1998/1201/p2041.html.

8. Ravin SSD, Naumann N, Robinson MR, et al. Sarcoidosis in Chronic Granulomatous Disease. Pediatrics;227(3): e590-e595. http://www.pediatricsdigest.mobi/con....full.pdf+html

9. "Blau Syndrome": NIH Genetic and Rare Diseases Information Center (GARD)

10. Henckaerts L, and Vermeire S. NOD2/CARD15 disease associations other than Crohn's disease. Inflam Bowel Dis. 2007;13(2):235-241. http://onlinelibrary.wiley.com/doi/1.../ibd.20066/pdf.

11. Gonda TA, Kim Y-I, Salas MC, et al. Folic Acid Increases Global DNA Methylation and Reduces Inflammation to Prevent Helicobacter-Associated Gastric Cancer in Mice. Gastroenterology. 2012; 142(4):824-833.

12. Dietary Supplement Fact Sheet: Folate. Office of Dietary Supplements, National Institutes of Health (NIH) http://ods.od.nih.gov/factsheets/Fol...thProfessional

13. Guagnozzi D, Cossu A, Viscido A, et al. Acute intestinal obstruction and NOD2/CARD15 mutations among italian Crohn's disease patients. Eur Rev for Med and Pharmacol Sci. 2004; 8:179-185. http://www.europeanreview.org/pdf/129.pdf

14. Gersemann M, Wehkamp J, and Stange EF. Innate immune dysfunction in inflammatory bowel disease. Journal of Internal Medicine. 2012; 271: 421–428. doi: 10.1111/j.1365-2796.2012.02515.x http://onlinelibrary.wiley.com/doi/1...12.02515.x/pdf

15. Russell RK, Wilson DC, and Satsangi J. Unravelling the complex genetics of inflammatory bowel disease. Arch Dis Child. 2004; 89:598-603. http://www.ncbi.nlm.nih.gov/pmc/arti...v089p00598.pdf

16. Naser SA, Arce M, Khaja A, Fernandez M, Naser N, Elwasila S, Thanigachalam S. Role of ATG16L, NOD2 and IL23R in Crohn’s disease pathogenesis. World J Gastroenterol. 2012 Feb 7;18(5):412-24. http://www.wjgnet.com/1007-9327/pdf/v18/i5/412.pdf

17. Gutierrez A. NOD2, ATG16L1 gene variants impact response to Crohn’s disease treatment. Gut. 2013. http://www.healio.com/gastroenterolo...ease-treatment

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06-01-2012, 07:43 PM   #1
David
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This is interesting considering mast cells are also found in abundance in people with strictures:

Hyperexpression of NOD2 in intestinal mast cells of Crohn's disease patients: preferential expression of inflammatory cell-recruiting molecules via NOD2 in mast cells
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