The NOD2 gene encodes a protein of 1040 amino acids, a member of the Nod1/Apaf-1 family with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs).  This protein is mainly expressed in Paneth cells in the small bowel and is involved in the innate immune response to bacterial pathogens.  It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing muramyl dipeptide (MDP) constituents of bacterial peptidoglycans and plays a key role in gastrointestinal immunity.  Upon stimulation, it recruits RIPK2 (Receptor-Interacting Serine-Threonine Kinase 2), which in turn recruits ubiquitin ligases as XIAP, BIRC2, BIRC3 and the LUBAC complex, triggering activation of MAP kinases and activation of NF-kappa-B signaling.  This leads to the activation of the transcription of hundreds of genes involved in immune response.

The NOD2 gene has been mapped to chromosome 16q12, comprising 12 coding exons.  More than 40 different mutations in the NOD2 gene have been associated with Crohn’s disease (CD).  Three of them are common; a frameshift mutation (Leu1007fsinsC), and two SNP mutations (Arg702Trp) and (Gly908Arg).  NOD2 deficiency increases TLR2-mediated activation of NF-κB resulting in a pro-inflammatory cytokine bias, which could contribute to the overwhelming inflammation seen in CD.  Also mutations within this gene have been associated with Blau syndrome, and development of several types of cancer.