Regulation of the LDL receptor in familial hypercholesterolemia

Dysregulation of the LDL receptor pathway causes the inherited metabolic disorder familial hypercholesterolemia, characterized by raised serum LDL and increased risk of coronary heart disease. Defects in the LDL receptor gene itself are the most frequent cause, and identification of the genetic defect is now considered a useful adjunct to clinical diagnosis, although care must be taken to ensure the variant is causal. Familial hypercholesterolemia is underdiagnosed, and although population screening is not considered cost effective, cascade screening of relatives of affected patients is underway and should allow effective preventative treatment. Defects in other genes can cause a very similar phenotype, for example, the genes for apolipoprotein B, the ligand for the LDL receptor, ARK a protein essential for internalization of:the receptor from the cell surface, and PCSK9, a protein that increases degradation of LDL receptor protein. Not all clinically diagnosed patients have a known defect suggesting that other genes remain to be discovered.