PCSK9

The PCSK9 gene provides instructions for making a protein that helps regulate the amount of cholesterol in the bloodstream. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals.

The PCSK9 protein appears to control the number of low-density lipoprotein receptors, which are proteins on the surface of cells. These receptors play a critical role in regulating blood cholesterol levels. The receptors bind to particles called low-density lipoproteins (LDLs), which are the primary carriers of cholesterol in the blood. Low-density lipoprotein receptors are particularly abundant in the liver, the organ responsible for removing most excess cholesterol from the body.

The number of low-density lipoprotein receptors on the surface of liver cells determines how quickly cholesterol (in the form of low-density lipoproteins) is removed from the bloodstream. Studies suggest that the PCSK9 protein helps control blood cholesterol levels by breaking down low-density lipoprotein receptors before they reach the cell surface.

hypercholesterolemia - caused by mutations in the PCSK9 gene

Researchers have identified several PCSK9 mutations that cause an inherited form of high cholesterol (hypercholesterolemia). These mutations change a single protein building block (amino acid) in the PCSK9 protein. Researchers describe the mutations responsible for hypercholesterolemia as "gain-of-function" because they appear to enhance the activity of the PCSK9 protein or give the protein a new, atypical function.

The overactive PCSK9 protein significantly reduces the number of low-density lipoprotein receptors on the surface of liver cells. Researchers speculate that the altered protein may cause these receptors to be broken down more quickly than usual. With fewer receptors to remove low-density lipoproteins from the blood, people with gain-of-function mutations in the PCSK9 gene have very high blood cholesterol levels. 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 PCSK9 gene

Other mutations in the PCSK9 gene result in reduced blood cholesterol levels (hypocholesterolemia). These genetic changes reduce the activity of the PCSK9 protein or decrease the amount of this protein that is produced in cells. Researchers describe this type of mutation as "loss-of-function." Loss-of-function mutations in the PCSK9 gene appear to be more common than gain-of-function mutations, which are responsible for hypercholesterolemia.

Loss-of-function mutations in the PCSK9 gene lead to an increase in the number of low-density lipoprotein receptors on the surface of liver cells. The extra receptors can remove low-density lipoproteins from the blood more quickly than usual, which decreases the amount of cholesterol circulating in the bloodstream. Studies suggest that people with reduced cholesterol levels caused by PCSK9 mutations have a significantly lower-than-average risk of developing heart disease.

Researchers suspect that normal changes (polymorphisms) in the PCSK9 gene are responsible for some of the variation in blood cholesterol levels among people without inherited cholesterol disorders. In particular, scientists are working to determine which polymorphisms are associated with relatively low levels of cholesterol in the blood and a reduced risk of heart disease.

Genetics Home Reference provides information about familial hypobetalipoproteinemia, which is also associated with changes in the PCSK9 gene.