Mutant Receptors for Low Density Lipoprotein in Familial Hypercholesterolemia
The concept of receptor-mediated metabolism of lipoproteins emerged from studies initiated in 1973 on human skin fibroblasts grown in culture1. These experiments were designed to elucidate the normal function of low density lipoprotein (LDL), about which little was known at that time. Biochemical studies showed that a specific cell surface receptor, the LDL receptor, mediates the binding, uptake and degradation of LDL, thus supplying almost all cells in the body with cholesterol. Detailed insight into the molecular mechanisms underlying this complex process was obtained from studies with fibroblasts derived from patients with the phenotype of homozygous familial hypercholesterolemia (FH). As in many other biological systems, the expression of a disease state in a defined cellular system was essential to the discovery of the causal factor: FH is now one of the best characterized genetic diseases at the molecular level. As will be outlined below, in FH several groups of mutations occur naturally in the structural gene for the LDL receptor which disrupt its normal function and lead to severe hypercholesterolemia, producing myocardial infarctions and premature atherosclerosis. Thus, the important role of lipoprotein receptors in normal physiology is underscored by the dramatic consequences of their functional absence.
KeywordsFamilial Hypercholesterolemia Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia Mature Receptor WHHL Rabbit
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