Familial Hypercholesterolemia (FH) is a hereditary disease. Individuals with FH typically have mutations affecting their LDL Receptor (see below). The result of these mutations is a higher than normal level of serum cholesterol. Individuals who are homozygous for the disease have very high levels of cholesterol in the blood and usually die of heart disease before age 20. People heterozygous for the disease have higher than normal cholesterol and are at high risk for heart attacks in their thirties and forties.

Cultured fibroblasts from FH individuals synthesize cholesterol at abnormally high levels in the presence of LDLs, compared to normal cells. This activity is linked to the enzyme HMG-CoA reductase, the major regulatory enzyme of cholesterol biosynthesis, which is allosterically inactivated by cholesterol. Cells from FH individuals have an impaired ability to take up cholesterol, via receptor mediated endocytosis, thus requiring endogenous synthesis. LDL levels in the bloodstream remain high, due to lack of uptake. High LDL levels favor oxidation of the components of the LDL and ultimately formation of atherosclerotic plaques.

Phenotypes of the LDL receptor mutations in FH individuals are as follows:

1. Reductions in amount of LDL receptor made;

2. LDL receptor is made, but it fails to migrate to plasma membrane;

3. LDL receptor is in plasma membrane, but it fails to bind LDL; and

4. LDL receptor is in plasma membrane and binds LDL, but it fails to cluster in coated pits.