Proprotein convertase subtilisin/kexin type 9
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 controls 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 is removed from the bloodstream. The PCSK9 protein breaks down low-density lipoprotein receptors before they reach the cell surface, so more cholesterol can remain in the bloodstream.
Researchers have identified more than 50 PCSK9 gene mutations that cause familial hypercholesterolemia. Most of these mutations change single protein building blocks (amino acids) in the PCSK9 protein. Researchers describe the mutations responsible for familial hypercholesterolemia as "gain-of-function" because they appear to enhance the activity of the PCSK9 protein.
The enhanced activity of the altered PCSK9 protein causes low-density lipoprotein receptors to be broken down more quickly than usual, reducing the number of receptors on the surface of liver cells. With fewer receptors to remove LDLs 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.
Most people with familial hypercholesterolemia inherit one altered copy of the PCSK9 gene from an affected parent and one normal copy of the gene from the other parent. These cases are associated with an increased risk of early heart disease, typically beginning in a person's forties or fifties. Rarely, a person with familial hypercholesterolemia is born with two mutated copies of the PCSK9 gene. This situation occurs when the person has two affected parents, each of whom passes on one altered copy of the gene. The presence of two PCSK9 gene mutations results in a more severe form of hypercholesterolemia that usually appears in childhood.
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 cause familial hypercholesterolemia (described above).
Loss-of-function mutations in the PCSK9 gene impair the break down of low-density lipoprotein receptors, which leads to an increase in the number of receptors on the surface of liver cells. The extra receptors can remove LDLs 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.