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The Journal of Lipid Research, Vol. 39, 658-669, March 1998
Copyright © 1998 by Lipid Research, Inc.

Original Article

Apolipoprotein E2 (Arg¹³⁶ Cys) mutation in the receptor binding domain of apoE is not associated with dominant type III hyperlipoproteinemia

Correspondence to: Winfried März.

Using apoE phenotyping by immunoblotting and apoE genotyping we identified four heterozygous carriers of a rare apolipoprotein (apo) E2 variant, apoE2 (Arg¹³⁶ Cys). ApoE2 (Arg¹³⁶ Cys) was not distinct from apoE2 (Arg¹⁵⁸ Cys) by phenotyping, but produced a unique pattern of bands on CfoI restriction typing of a 244 bp apoE gene fragment. Two of the four apoE2 (Arg¹³⁶ Cys)/3 heterozygotes had elevated triglycerides, two were normolipidemic. The composition of very low density lipoproteins (VLDL) was normal in each of the four apoE2 (Arg¹³⁶ Cys) carriers, regardless of the triglyceride concentrations. None of the apoE2 (Arg¹³⁶ Cys) carriers displayed a broad ß-band and none revealed ß-migrating particles in the VLDL. The two hypertriglyceridemic carriers of apoE2 (Arg¹³⁶ Cys) were, therefore, classified as having type IV rather than type III hyperlipoproteinemia. LDL receptor binding activities were studied using recombinant apoE loaded to dimyristoylphosphatidylcholine (DMPC) vesicles and to VLDL and from an apoE-deficient individual. LDL receptor binding of apoE2 (Arg¹³⁶ Cys) was 14% of apoE3 and was thus higher than that of apoE2 (Arg¹⁵⁸ Cys). Both apoE2 (Arg¹³⁶ Cys) and apoE2 (Arg¹⁵⁸ Cys) displayed substantial heparin binding (61 and 53% of apoE3, respectively). As the dominant apoE variants known so far are characterized by more pronounced reductions of heparin binding, we suggest that apoE2 (Arg¹³⁶ Cys) is not associated with dominant expression of type III hyperlipoproteinemia.

These findings lend support to the concept that apoE variants predisposing to dominant type III hyperlipoproteinemia differ from recessive mutations by a more severe defect in heparin binding.—März, W., M. M. Hoffmann, H. Scharnagl, E. Fisher, M. Chen, M. Nauck, G. Feussner, and H. Wieland. Apolipoprotein E2 (Arg¹³⁶ Cys) mutation in the receptor binding domain of apoE is not associated with dominant type III hyperlipoproteinemia. J. Lipid Res. 1998. 39: 658–669.

Supplementary key words: very low density lipoproteins, apolipoprotein B, low density lipoprotein receptor, hypercholesterolemia, hypertriglyceridemia, dysbetalipoproteinemia, heparan sulfate proteoglycans

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