C3

The C3 gene provides instructions for making a protein called complement component 3 (or simply C3). This protein plays a key role in a part of the body's immune response known as the complement system. The complement system is a group of proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues.

The C3 protein is essential for activating the complement system. The presence of foreign invaders triggers the C3 protein to be cut (cleaved) into two smaller pieces. One of these pieces, called C3b, interacts with several other proteins on the surface of cells to trigger the complement system's response. This process must be carefully regulated so the complement system targets only unwanted materials and does not attack the body's healthy cells.

Researchers have identified two major forms (allotypes) of the C3 protein, which are known as C3S and C3F. In the general population, C3S is more common than C3F. The two allotypes differ by a single protein building block (amino acid), although it is unclear whether they function differently.

dense deposit disease - caused by mutations in the C3 gene

At least one mutation in the C3 gene has been found to cause dense deposit disease. This condition, which was formerly known as membranoproliferative glomerulonephritis type II, is a form of progressive kidney (renal) disease. The identified mutation deletes two amino acids from the C3 protein. This genetic change is described as a "gain-of-function" mutation because it leads to abnormal activation of the complement system. The overactive system creates debris that builds up in and damages certain structures in the kidneys. These structures, called glomeruli, are clusters of tiny blood vessels that help filter waste products from the blood. Damage to glomeruli prevents the kidneys from filtering waste products normally and can lead to end-stage renal disease (ESRD), a life-threatening failure of kidney function.

Several normal variants (polymorphisms) in the C3 gene have also been associated with an increased risk of developing dense deposit disease. In particular, the C3F allotype is seen more frequently in people with this condition than in the general population. Researchers are working to determine how the C3F allotype influences disease risk.

other disorders - caused by mutations in the C3 gene

At least eight mutations in the C3 gene have been found to cause C3 deficiency, a condition characterized by recurrent bacterial infections. The genetic changes responsible for C3 deficiency are described as "loss-of-function" mutations because they prevent normal activation of the complement system. As a result, the immune system is less able to protect the body against foreign invaders (such as bacteria).

Several mutations in the C3 gene also appear to increase the risk of a kidney disease called atypical hemolytic-uremic syndrome. Studies suggest that many of these genetic changes alter the C3 protein's ability to attach (bind) to other proteins, leading to abnormal activation of the complement system. The overactive system attacks endothelial cells, which line small blood vessels in the kidneys. Damage to these cells often leads to kidney failure and ESRD in people with atypical hemolytic-uremic syndrome.

Although genetic changes increase the risk of atypical hemolytic-uremic syndrome, studies suggest that they are often not sufficient to cause the disease. In people with C3 gene mutations, the signs and symptoms of the disorder may be triggered by factors such as certain medications (such as anti-cancer drugs), chronic diseases, viral or bacterial infections, cancers, organ transplantation, or pregnancy.

Changes in the C3 gene have also been associated with an increased risk of an eye disorder called age-related macular degeneration (AMD), which is a leading cause of vision loss in the elderly. Specifically, the C3F allotype is seen more frequently in people with AMD than in the general population. It is unclear how the C3F allotype is related to the risk of AMD, although the condition can be associated with uncontrolled activation of the complement system. A combination of genetic and environmental factors likely determines the risk of developing this complex eye disorder.

Genetics Home Reference provides information about these additional conditions, which are also associated with changes in the C3 gene:

• age-related macular degeneration
• atypical hemolytic-uremic syndrome