The Apolipoprotein E Cys-142 Mutant: Role in Dominant Inheritance of Type III Hyperlipoproteinemia and Expression in Transgenic Mice
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.
KeywordsCholesterol Agarose Cysteine Heparin Electrophoresis
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- Horie, YS, Fazio, S, Westerlund, JR, Weisgraber, KH, and Rall, SC, Jr. (1992) The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J Biol Chem 267: 1962–1968Google Scholar
- Mahley, RW, and Rall, SC, Jr. in The Metabolic Basis of Inherited Disease, 6th Edition (eds Scriver, CR, Beaudet, AL, Sly, WS, and Valle, D ) 1195–1213 ( McGraw-Hill, New York, 1989 )Google Scholar
- Rall, SC, Jr., Newhouse, YM, Clarke, HRG, Weisgraber, KH, McCarthy, BJ, Mahley, RW, and Bersot, TP (1989) Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3: structure and genetics of an apolipoprotein E3 variant. J Clin Invest 83: 1095–1101Google Scholar
- Simonet, WS, Bucay, N, Lauer, SJ, Wirak, DO, Stevens, ME, Weisgraber, KH, Pitas, RE, and Taylor, JM (1990) In the absence of a downstream element, the apolipoprotein E gene is expressed at high levels in kidneys of transgenic mice. J Biol Chem 265: 10809–10812Google Scholar
- Vogel, T, Weisgraber, KH, Zeevi, MI, Ben-Artzi, H, Levanon, AZ, Rall, SC, Jr., Innerarity, TL, Hui, DY, Taylor, JM, Kanner, D, Yavin, Z, Amit, B, Aviv, H, Gorecki, M, and Mahley, RW (1985) Human apolipoprotein E expression in Escherichia coli: structural and functional identity of the bacterially produced protein with plasma apolipoprotein E. Proc Natl Acad Sci USA 82: 8696–8700CrossRefGoogle Scholar
- Weisgraber, KH, Innerarity, TL, Harder, KJ, Mahley, RW, Milne, RW, Marcel, YL, and Sparrow, JT (1983) The receptor-binding domain of human apolipoprotein E. Monoclonal antibody inhibition of binding. J Biol Chem 258: 12348–12354Google Scholar
- Weisgraber, KH, Rall, SC, Jr., Mahley, RW, Milne, RW, Marcel, YL, and Sparrow, JT (1986) Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J Biol Chem 261: 2068–2076Google Scholar