The Apolipoprotein E Cys-142 Mutant: Role in Dominant Inheritance of Type III Hyperlipoproteinemia and Expression in Transgenic Mice

Abstract

Type III hyperlipoproteinemia (HLP) is a genetic disorder of lipid metabolism in humans in which the primary molecular defect is a mutation(s) in apolipoprotein (apo) E that causes defective interaction of apoE with lipoprotein receptors and an accumulation of cholesterol-rich β-VLDL in the blood (Mahley and Rall, 1989). Most often, type III HLP is associated with homozygosity for an apoE mutant that has cysteine instead of arginine at residue 158, i.e., with recessive inheritance. Many rare mutants of apoE have now been described (Fig. 1), some of which are also associated with type III HLP. In most of these rare instances, type III HLP is transmitted in a dominant fashion, i.e., heterozygosity for the apoE mutant is sufficient for expression of the disorder. One of these rare apoE variants (cysteine instead of arginine at residue 142) has been found in a single family in which seven members spanning four generations are heterozygous for this apoE variant and all seven have type III HLP (Havel et al. 1983; Rall et al. 1989). Because of the unusual nature of the disorder in this family, we undertook investigations of the properties of the apoE Cys-142 mutant to determine its role in the expression of type III HLP.

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