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  • Familial hypercholesterolemia (FH) is characterized clinically by (a) an elevated concentration of LDL, the major cholesterol-transport lipoprotein in human plasma; (b) deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas); and (c) inheritance as an autosomal dominant trait with a gene dosage effect—that is, homozygotes are more severely affected than are heterozygotes.

  • Heterozygotes number about 1 in 500 persons, placing FH among the most common inborn errors of metabolism. Heterozygotes have twofold elevations in plasma cholesterol (350 to 550 mg/dl) from birth. Tendon xanthomas and coronary atherosclerosis develop after ages 20 and 30, respectively.

  • Homozygotes number 1 in 1 million persons. They have severe hypercholesterolemia (650 to 1000 mg/dl). Cutaneous xanthomas appear within the first 4 years of life. Coronary heart disease begins in childhood and frequently causes death from myocardial infarction before age 20.

  • The primary defect in FH is a mutation in the gene specifying the receptor for plasma LDL. Located on the surfaces of cells in the liver and other organs, the LDL receptor binds LDL and facilitates its uptake by receptor-mediated endocytosis and its delivery to lysosomes, where the LDL is degraded and its cholesterol is released for metabolic use. When LDL receptors are deficient, the rate of removal of LDL from plasma declines, and the level of LDL rises in inverse proportion to the receptor number. The excess plasma LDL is deposited in scavenger cells and other cell types, which produces xanthomas and atheromas.

  • The LDL receptor gene is on the short arm of chromosome 19. It comprises 18 exons that span 45 kb. The gene encodes a single-chain glycoprotein that contains 839 amino acids in its mature form. Five classes of mutations at the LDL receptor locus have been identified based on phenotypic behavior of the mutant proteins. Each class has been subdivided into multiple alleles through molecular characterization. More than 420 different mutant alleles distort receptor function in meaningful ways. Class 1 alleles fail to produce an immunoprecipitable protein (null alleles). Class 2 alleles, the most common, encode proteins blocked in intracellular transport between the ER and the Golgi complex (transport-defective alleles). Class 3 alleles encode proteins that are transported to the cell surface, but fail to bind LDL normally (binding-defective alleles). Class 4 alleles, the rarest, encode proteins that reach the cell surface and bind LDL normally, but fail to cluster in coated pits and hence do not internalize bound LDL (internalization-defective alleles). Class 5 alleles encode receptors that bind and internalize LDL in coated pits, but cannot discharge the LDL in the endosome and thus fail to recycle to the cell surface (recycling-defective alleles).

  • FH heterozygotes have one normal allele and one mutant allele at the LDL receptor locus; hence, their cells are able to bind and take up LDL at approximately half the normal rate. Phenotypic homozygotes possess two mutant alleles at the LDL receptor locus; hence, their cells show a total or near-total inability to bind ...

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