APOB

The APOB gene provides instructions for making two versions of the apolipoprotein B protein, a short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-100. Both of these proteins are components of lipoproteins, which are particles that carry fats and fat-like substances (such as cholesterol) in the blood.

Apolipoprotein B-48 is produced in the intestine, where it is a building block of a type of lipoprotein called a chylomicron. As food is digested after a meal, chylomicrons are formed to carry fat and cholesterol from the intestine into the bloodstream. Chylomicrons are also necessary for the absorption of certain fat-soluble vitamins such as vitamin E and vitamin A.

Apolipoprotein B-100, which is produced in the liver, is a component of several other types of lipoproteins. Specifically, this protein is a building block of very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs). These related molecules all transport fats and cholesterol in the bloodstream.

Low-density lipoproteins are the primary carriers of cholesterol in the blood. Apolipoprotein B-100 allows these particles to attach to specific receptors on the surface of cells, particularly in the liver. The receptors transport low-density lipoproteins into the cell, where they are broken down to release cholesterol. The cholesterol is then used by the cell, stored, or removed from the body.

hypercholesterolemia - caused by mutations in the APOB gene

At least five mutations in the APOB gene are known to cause a form of inherited hypercholesterolemia called familial defective apolipoprotein B-100 (FDB). Each of these mutations changes a single protein building block (amino acid) in a critical region of apolipoprotein B-100. The altered protein prevents low-density lipoproteins from effectively binding to their receptors on the surface of cells. As a result, fewer low-density lipoproteins are removed from the blood and cholesterol levels are much higher than normal. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and arteries that supply blood to the heart (coronary arteries). A buildup of cholesterol in the walls of coronary arteries greatly increases a person's risk of having a heart attack.

other disorders - associated with the APOB gene

Mutations in the APOB gene are responsible for some cases of an uncommon disorder called familial hypobetalipoproteinemia (FHBL), which is characterized by extremely low levels of apolipoprotein B and cholesterol in the blood (hypocholesterolemia). Children with this condition tend to grow slowly and have trouble gaining weight. They often have difficulty absorbing fat from their diet and may have very low levels of fat-soluble vitamins such as vitamin E and vitamin A. A shortage of these vitamins can lead to problems with the nervous system and a disorder called retinitis pigmentosa that causes vision loss.

About 60 APOB mutations have been identified in people with familial hypobetalipoproteinemia. Most of these genetic changes severely reduce the amount of functional apolipoprotein B that is produced within cells. Other mutations lead to the production of an abnormally short version of apolipoprotein B that is quickly broken down. Because apolipoprotein B is an essential component of low-density lipoproteins, a reduction in the amount of this protein leads to a shortage of low-density lipoproteins in the blood and extremely low blood cholesterol levels. The body requires an adequate amount of cholesterol to build cell membranes, make certain hormones, and produce compounds that aid in fat digestion.

Researchers are studying other variations (polymorphisms) in the APOB gene that may influence heart disease risk in people without inherited cholesterol disorders. Some studies have found that certain polymorphisms are associated with higher levels of low-density lipoproteins in the blood and an increased chance of developing or dying of heart disease. Other studies, however, have not shown such an association. It is clear that a large number of genetic and lifestyle factors, many of which remain unknown, determine the risk of developing this complex condition.