The article by Hobbs, Brown, and Goldstein provides an overview of the molecular genetics of the low-density lipoprotein (LDL) receptor gene in familial hypercholesterolemia (FH). FH is an autosomal dominant disorder characterized by elevated plasma levels of LDL, leading to premature coronary atherosclerosis. The authors describe 79 additional mutations to the 150 known mutations in the LDL receptor gene, which have provided insights into the structure-function relationship of the receptor protein and the clinical manifestations of FH. The LDL receptor gene is regulated by feedback suppression mediated by intracellular cholesterol, with specific DNA sequences responsible for sterol-regulated expression. The mutations are categorized into five classes: Class 2 mutations affect the ligand binding domain, Class 3 mutations affect ligand binding but not transport, Class 4 mutations affect internalization, Class 5 mutations affect recycling, and Class 6 mutations affect promoter regions. The article also discusses the population genetics of FH, including founder effects and recurrent mutations, and highlights the diagnostic relevance of molecular analysis in different populations. Additionally, it explores the biological insights gained from studying LDL receptor mutations, such as the role of Alu repeats in gene rearrangements, the importance of transport-defective mutations in other genetic diseases, and the targeting signals for receptors that cluster in coated pits. The multifunctionality of receptors, exemplified by the LDL receptor and related proteins, is also discussed.The article by Hobbs, Brown, and Goldstein provides an overview of the molecular genetics of the low-density lipoprotein (LDL) receptor gene in familial hypercholesterolemia (FH). FH is an autosomal dominant disorder characterized by elevated plasma levels of LDL, leading to premature coronary atherosclerosis. The authors describe 79 additional mutations to the 150 known mutations in the LDL receptor gene, which have provided insights into the structure-function relationship of the receptor protein and the clinical manifestations of FH. The LDL receptor gene is regulated by feedback suppression mediated by intracellular cholesterol, with specific DNA sequences responsible for sterol-regulated expression. The mutations are categorized into five classes: Class 2 mutations affect the ligand binding domain, Class 3 mutations affect ligand binding but not transport, Class 4 mutations affect internalization, Class 5 mutations affect recycling, and Class 6 mutations affect promoter regions. The article also discusses the population genetics of FH, including founder effects and recurrent mutations, and highlights the diagnostic relevance of molecular analysis in different populations. Additionally, it explores the biological insights gained from studying LDL receptor mutations, such as the role of Alu repeats in gene rearrangements, the importance of transport-defective mutations in other genetic diseases, and the targeting signals for receptors that cluster in coated pits. The multifunctionality of receptors, exemplified by the LDL receptor and related proteins, is also discussed.