Often in medicine we learn the function of a crucial protein not by study of normal physiology, but rather by studying the disruptions that occur when the gene for that protein undergoes mutation. This approach was particularly helpful in the case of the low density lipoprotein (LDL) receptor, which controls the level of LDL in blood. This receptor, located on the surfaces of hepatocytes and other cells, binds LDL and other lipoproteins that contain apolipoprotein (apo) B-100 or apo E. Binding leads to cellular uptake and degradation of the lipoprotein through receptor-mediated endocytosis'1'. Mutations in the gene encoding the LDL receptor occur in patients with familial hypercholesterolaemia (FH)'2'. Individuals with the heterozygous form of this disease have one normal LDL receptor gene and one defective gene. Their plasma LDL levels are about 2-fold above normal, and they typically have heart attacks before age 60 years Rare individuals (one in 1 million) inherit two mutant LDL receptor genes. These FH homozygotes have no normal LDL receptor genes. Their plasma LDL levels are 6-to 10-fold above normal, and they typically have heart attacks before age 20 years.

The prevalence of LDL receptor mutations is about one in 1000 genes (one in 500 individuals) in most countries throughout the world. A higher incidence is observed in certain populations, owing to founder effects. These include French Canadians, South Africans of Dutch and German extraction, and Lebanese Christians'3'. Although all FH patients have mutations in the LDL receptor gene, not all of the mutations are the same. In a genetically heterogeneous country such as the United States, most families with FH have different mutations of the LDL receptor locus Some of these mutations totally destroy the function of the LDL receptor. Others have less severe effects'3'.