Apolipoprotein E2(Arg158----Cys) frequency in a hyperlipidemic French-Canadian population of apolipoprotein E2/2 subjects. Determination by synthetic oligonucleotide probes.

Abstract

An underlying cause of type III hyperllpoproteinemia Is the presence of variant forms of apolipoprotein (apo) E that are defective in binding to apo B,E low density llpoprotein receptors. This disorder Is associated almost exclusively with the apo E2/ 2 phenotype. However, structural and functional heterogeneity have been demonstrated within this phenotype. The apo E2(Arg 1s8 -»Cys) variant, displaying 1 % of normal apo E3 binding activity, Is the most defective known form. In this study, we describe a method in which a pair of 19-mer synthetic oligonucleotide probes were used to distinguish between DNA coding for arglnlne or cystelne at position 158 In apo E. The specificity of the probes was demonstrated by using DNA from subjects whose apo E protein sequence or phenotype was known. The probes were used to screen a French-Canadian population of 34 apo E2/2 subjects to determine the frequency of the apo E2(Arg 1M ->Cys) variant All 34 subjects, most of whom displayed clinical or biochemical features of type III hyperllpoproteinemia, were found to be homozygous for apo E2(Arg 1sr ->Cys), strongly suggesting that this variant Is the most common form of apo E2 within this ethnic and clinical population. In addition, the utility of this approach In detecting new apo E mutants was demonstrated when DNA from one of the apo E3/3 control subjects, whose family has a history of hyperllpldemla and coronary artery disease, reacted with both probes. This result suggests that this subject Is heterozygous for normal apo E3 and a new apo E3 variant that Is likely to be functionally equivalent to apo E2(Arg 1M ->Cys). (Arteriosclerosis 9:50-57, January/February 1989) H uman apolipoprotein (apo) E is a component of several classes of plasma lipoproteins and, because of its ability to interact with lipoprotein receptors, apo E plays an important role in directing the metabolism of triglyceride-and cholesterol-containing lipoproteins.1 The structures of the protein and its gene are known. 2314 A combination of experimental approaches has demonstrated that a region of the protein in the vicinity of residues 140 to 160 is critical for interaction with apo B,E LDL receptors (for review, see Reference 5). Apo E, which exhibits a genetically determined polymorphism at the level of the structural gene, has several variants, 5 many of which display defective receptor binding activity. heterogeneity results in six phenotypes: E2/2, E3/3, E4/4, E4/2, E4/3, and E3/2. 6 The apo E3/3 phenotype is the most prevalent one in several different populations.7 - 13The most common variants differ by arginine-cysteine interchanges at positions 112 and 158. The apo E4, apo E3, and apo E2 variants contain Arg/Arg, Cys/Arg, and Cys/Cys, respectively, at positions 112/158.

Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

“…Four individual mutations give electrophoretically separated bands at the E2 position. Using the isoelectric focusing techniques [45] at least four different bands (corresponding to different ApoE2 conformational status) have been identified: E2 (arg158-to-cys) [46], E2 (lys146-to-gln) [47], E2 (arg145-to-cys), and E2-Christchurch (arg136-to-ser) [48]. E2 (arg158-to-cys) is the most common of all four.…”

Effects of the apolipoprotein E polymorphism on levels of lipids, lipoproteins, and apolipoproteins among Mexican-Americans in Starr County, Texas.

“…25 - 26 The E3 isoform has amino acids cysteine and arginine at positions 112 and 158, respectively. E4 has arginine at both positions.…”

Genetic burden linked to founder effects in Saguenay–Lac-Saint-Jean illustrates the importance of genetic screening test availability

“…80 Its estimated worldwide prevalence is 1/5000 but it is fivefold more frequent in the SLSJ due to a higher prevalence of APOE2, as estimated from the regional sample of the Quebec Heart Health Survey in 1991 81 and other sources. [82][83][84] LPLD (MIM: 238600) is the main cause of the familial chylomicronemia syndrome (FCS) which is due to the presence of null variants in the LPL gene or in genes directly affecting LPL bioavailability, such as APOC2, GPIHPB1, APOA5 or MLF1. 85 LPLD is characterised by chylomicronemia (very severe hypertriglyceridemia), lipemia retinalis, eruptive xanthomas, and increased risk of recurrent acute pancreatitis and other morbidities.…”