A human hereditary disease characterized by an elevation in the plasma concentration of low-density lipoproteins (LDLs). FH is inherited as an autosomal dominant, and the gene responsible resides on the short arm of chromosome 19 at region 13.2–3. The prevalence of heterozygotes is about 1/500 among American, European, and Japanese populations, and this makes FH among the most common hereditary diseases. Homozygotes are rare (1 per million in the U.S.A.). The gene is 45 kilobase pairs long and contains 18 exons that encode the low-density lipoprotein receptor (LDLR). This glycoprotein is made up of 839 amino acids, which are grouped into five domains. These are (1) the ligand-binding domain, (2) the domain showing homology to the precursor of the epidermal growth factor (q.v.), (3) the domain containing bound chains of carbohydrates, (4) the transmembrane domain, and (5) the cytoplasmic domain. The first domain is negatively charged, and it binds to the positively charged LDL particle. The second is essential for the normal recycling of the receptors. The third stabilizes the receptor. The fourth contains hydrophobic amino acids, and it spans the plasma membrane and anchors the LDLR to the cell. The fifth is necessary for clustering the receptors into coated pits. There is a direct relationship between the structural domains and exon sequences. For example, domain 2 is encoded by exons 7–14 and domain 5 by exons 17 and 18. Mutations of the LDLR gene result from insertions, deletions, and missense or nonsense mutations. Most mutations prevent the synthesis of LDLRs. The second most common mutant class generates LDLRs that cannot exit the endoplasmic reticulum. In a third mutant class LDLRs are transported to the cell surface, but cannot bind LDL particles. Finally, there is a rare group of mutant LDLRs that can bind LDL particles, but cannot cluster into coated pits. In most heterozygotes, receptor activity is one-half normal and in homozygotes LDLRs are absent. Deficient receptor-mediated endocytosis (q.v.) causes LDLs to accumulate in the plasma. Cholesterol is deposited on arterial walls and atherosclerosis results. The disease is far more serious in homozygotes than in heterozygotes. See Chronology, 1975, Goldstein and Brown; plasma lipoproteins, WHHL rabbit.
Subjects: Genetics and Genomics.