The LDL receptor is a cell surface transmembrane protein that mediates the uptake and lysosomal degradation of plasma LDL, providing cholesterol to cells. Mutations in the LDL receptor gene cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by elevated plasma LDL levels and premature coronary atherosclerosis. To date, 150 mutations in the LDL receptor gene have been characterized, including 79 newly identified mutations. These mutations have provided insights into the structure/function relationship of the receptor protein and the clinical manifestations of FH. The LDL receptor gene is located on chromosome 19 and spans 45 kb, consisting of 18 exons and 17 introns. Exon 1 encodes the signal sequence, while exons 2–6 encode the ligand binding domain, which contains seven tandem repeats of a 40-amino acid, cysteine-rich sequence. Exons 7–14 encode a region that shares sequence identity with the human epidermal growth factor (EGF) precursor gene. The LDL receptor is regulated by intracellular cholesterol, with the 5'-flanking region containing cis-acting DNA sequences responsible for sterol-regulated expression. LDL receptor mutations have been classified into five functional classes: null alleles, transport-defective alleles, binding-defective alleles, internalization-defective alleles, and recycling-defective alleles. Class 1 mutations fail to produce immunoprecipitable LDL receptor protein. Class 2 mutations are the most common, affecting transport between the endoplasmic reticulum and the Golgi apparatus. Class 3 mutations result in binding defects, while Class 4 mutations impair internalization, and Class 5 mutations prevent recycling of the receptor. Recurrent mutations, such as those involving CpG dinucleotides, are common in certain populations. Founder effects have led to the prevalence of a small number of mutations in specific populations, such as Ashkenazi Jews, French Canadians, and Finns. These mutations can be detected through DNA screening, allowing for the diagnosis of FH in these populations. The study of LDL receptor mutations has provided insights into the role of Alu repeats in gene rearrangements and the importance of targeting signals in receptor function. Transport-defective mutations are a frequent cause of FH and other genetic diseases, highlighting the importance of proper protein folding and trafficking. The LDL receptor's ability to bind multiple ligands is due to its modular structure, with different repeats responsible for binding different ligands. The clinical variability in FH is influenced by the nature of the LDL receptor gene mutation, with some mutations leading to less severe clinical outcomes. Genetic analysis has suggested the presence of a suppressor gene that may reduce the effects of LDL receptor mutations. The study of LDL receptor mutations has also provided insights into the function of other cell surface and secreted proteins, highlighting the importance of proper trafficking and folding in cellular function.The LDL receptor is a cell surface transmembrane protein that mediates the uptake and lysosomal degradation of plasma LDL, providing cholesterol to cells. Mutations in the LDL receptor gene cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by elevated plasma LDL levels and premature coronary atherosclerosis. To date, 150 mutations in the LDL receptor gene have been characterized, including 79 newly identified mutations. These mutations have provided insights into the structure/function relationship of the receptor protein and the clinical manifestations of FH. The LDL receptor gene is located on chromosome 19 and spans 45 kb, consisting of 18 exons and 17 introns. Exon 1 encodes the signal sequence, while exons 2–6 encode the ligand binding domain, which contains seven tandem repeats of a 40-amino acid, cysteine-rich sequence. Exons 7–14 encode a region that shares sequence identity with the human epidermal growth factor (EGF) precursor gene. The LDL receptor is regulated by intracellular cholesterol, with the 5'-flanking region containing cis-acting DNA sequences responsible for sterol-regulated expression. LDL receptor mutations have been classified into five functional classes: null alleles, transport-defective alleles, binding-defective alleles, internalization-defective alleles, and recycling-defective alleles. Class 1 mutations fail to produce immunoprecipitable LDL receptor protein. Class 2 mutations are the most common, affecting transport between the endoplasmic reticulum and the Golgi apparatus. Class 3 mutations result in binding defects, while Class 4 mutations impair internalization, and Class 5 mutations prevent recycling of the receptor. Recurrent mutations, such as those involving CpG dinucleotides, are common in certain populations. Founder effects have led to the prevalence of a small number of mutations in specific populations, such as Ashkenazi Jews, French Canadians, and Finns. These mutations can be detected through DNA screening, allowing for the diagnosis of FH in these populations. The study of LDL receptor mutations has provided insights into the role of Alu repeats in gene rearrangements and the importance of targeting signals in receptor function. Transport-defective mutations are a frequent cause of FH and other genetic diseases, highlighting the importance of proper protein folding and trafficking. The LDL receptor's ability to bind multiple ligands is due to its modular structure, with different repeats responsible for binding different ligands. The clinical variability in FH is influenced by the nature of the LDL receptor gene mutation, with some mutations leading to less severe clinical outcomes. Genetic analysis has suggested the presence of a suppressor gene that may reduce the effects of LDL receptor mutations. The study of LDL receptor mutations has also provided insights into the function of other cell surface and secreted proteins, highlighting the importance of proper trafficking and folding in cellular function.