NOD2 gene

The NOD2 gene (previously known as CARD15) provides instructions for making a protein that plays an important role in immune system function. The NOD2 protein is active in some types of immune system cells (including monocytes, macrophages, and dendritic cells), which help protect the body against foreign invaders such as bacteria and viruses. The protein is also active in several types of epithelial cells, including Paneth cells, which are found in the lining of the intestine. These cells help defend the intestinal wall against bacterial infection.

The NOD2 protein has several critical functions in defending the body against foreign invaders. The protein is involved in recognizing certain bacteria and stimulating the immune system to respond appropriately. When triggered by specific substances produced by bacteria, the NOD2 protein turns on (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. An inflammatory reaction occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair.
The NOD2 protein also appears to play a role in a process called autophagy, which cells use to surround and destroy bacteria, viruses, and other harmful substances. In addition to protecting cells from infection, autophagy is used to recycle worn-out cell parts and break down certain proteins when they are no longer needed. This process is also involved in the self-destruction of cells (apoptosis).

Blau syndrome
At least 22 mutations in the NOD2 gene have been found to cause Blau syndrome, an inflammatory disorder that begins in childhood and primarily affects the skin, joints, and eyes. These mutations change single protein building blocks (amino acids) in the NOD2 protein. All of these mutations result in a version of the NOD2 protein that is overactive, which can trigger an abnormal inflammatory reaction and cause swelling and irritation. However, it is unclear how the abnormally active protein causes the specific pattern of inflammation affecting the skin, joints, and eyes that is characteristic of Blau syndrome.
NOD2 gene mutations can also cause early-onset sarcoidosis, a similar condition that some researchers consider to be a noninherited version of Blau syndrome.

Crohn disease
Variations in the NOD2 gene have been associated with an increased risk of Crohn disease, a complex disorder that causes inflammation of the digestive system. In particular, NOD2 gene changes are associated with a form of Crohn disease that affects the lower part of the small intestine (the ileum) and the colon in populations of northern European descent. The three most common NOD2 variations are found in about 40 percent of all people with Crohn disease. The most common of these, written as 3020insC or 1007fs, leads to the production of a NOD2 protein that is slightly shorter than normal. Other common variations change single amino acids in the NOD2 protein. It is unclear how these genetic changes increase the risk of developing Crohn disease. Studies suggest that changes in the NOD2 gene prevent the protein from recognizing bacteria appropriately, allowing these microbes to grow unchecked and invade cells that line the intestine. An abnormal immune response to these bacteria may contribute to inflammation and the digestive problems characteristic of Crohn disease.

Yao syndrome
Several variations in the NOD2 gene increase the risk of developing Yao syndrome, a disorder that causes episodes of fever and abnormal inflammation affecting many parts of the body. Most people with this condition have a variation in the NOD2 gene written as IVS8+158, which is located in a region of the gene called intron 8. Another relatively common NOD2 gene variation in people with Yao syndrome replaces the amino acid arginine with the amino acid tryptophan at position 702 in the NOD2 protein (written as Arg702Trp or R702W). These variations have also been identified in some people with Crohn disease (described above). About 20 percent of people with Yao syndrome have both the IVS8+158 and R702W variations, and some affected individuals have additional variations in the NOD2 gene.
The effects of having one, two, or more variations in the NOD2 gene is unclear, although studies suggest that these genetic changes may alter the activity (expression) of the NOD2 gene. It is unknown how these variations might contribute to abnormal inflammation in people with Yao syndrome. Researchers suspect that environmental factors such as infections may also play a role in triggering the disease in people with genetic variants that increase their risk.

Cancers
A few studies have suggested a possible association between changes in the NOD2 gene, particularly the common variation 3020insC (described above), and the development of several types of cancer. Although some of these studies found an increased risk of cancer in people with a NOD2 gene variation, other research found no such association. It is unclear how changes in this gene might contribute to cancer risk.

Other disorders
Several studies have considered variations in the NOD2 gene as a possible risk factor for a condition called graft-versus-host disease (GVHD). GVHD 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. GVHD is the term used to describe this potentially severe reaction.
A few studies have suggested that variations in the NOD2 gene influence the risk of developing severe complications of GVHD following an allogeneic stem cell transplant. The presence of NOD2 gene variations in both the stem cell donor and the recipient is associated with the greatest risk of a severe reaction. However, other research has found no relationship between NOD2 gene changes and the risk of developing GVHD.

Chromosomal Location
Cytogenetic Location: 16q12.1, which is the long (q) arm of chromosome 16 at position 12.