Low-density lipoprotein receptors play a critical role in regulating the amount of cholesterol in the blood. They are particularly abundant in the liver, which is 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. Mutations in the LDLR gene cause a form of high cholesterol called familial hypercholesterolemia.
More than 2, mutations have been identified in this gene. Some of these genetic changes reduce the number of low-density lipoprotein receptors produced within cells. Other mutations disrupt the receptor's ability to remove LDLs from the blood.
As a result, people with mutations in the LDLR 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 LDLR 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 LDLR 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 LDLR gene mutations results in a more severe form of hypercholesterolemia that usually appears in childhood.
A mutation in the LDL receptor gene can result in elevated cholesterol. LDL then gets into the artery walls, where it can harden and narrow the passages in the arteries.
Familial hypercholesterolemia FH is an inherited disorder that causes high levels of LDLs to be present in the body and is a disorder that is often caused by a mutated LDL receptor gene. FH can lead to early cardiovascular disease and heart attacks at a young age.
Most people with FH are unaware that they have this condition and may not find out until they have suffered a heart attack. The mature LDL-receptor is subsequently guided to the "coated pits" on the cell surface. These specialized areas of the cell membrane are rich in clathrin and interact with the LDL-receptor protein. Within 3 to 5 minutes of its formation, the LDL-particle-receptor complex is internalized through endocytosis and is further metabolized through the receptor-mediated endocytosis pathway.
Mutations in the gene coding for the LDL-receptor can interfere to a varying extent with all the different stages of the posttranslational processing, binding, uptake, and subsequent dissociation of the LDL-particle-LDL-receptor complex, but invariably the mutations lead to familial hypercholesterolemia.
Thus, mutations in the LDL-receptor gene give rise to a substantially varying clinical expression of familial hypercholesterolemia.
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