Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia.

Wardell, Mark R.; Brennan, Stephen O.; Janus, Edward; Fraser, Robin; Carrell, Robin W.

doi:10.1172/jci113096

Cited by 139 publications

(58 citation statements)

References 54 publications

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“…20 The results are also consistent with the Funke et al study 29 in which DNAs from six apo E2/2 subjects and seven subjects heterozygous for apo E2 were examined with oligonucleotide probes. The DNA from each of the seven heterozygotes reacted with a Cys-158 probe.…”

supporting

confidence: 87%

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

et al. 1989

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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.

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supporting

confidence: 87%

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

et al. 1989

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“…Lipoprotein electrophoresis was performed according to the Helena Laboratories method on cellulose acetate strips (Chemac Laboratories Ltd., New Zealand) (9)(10)(11)17 ).…”

Section: Additional Analysesmentioning

confidence: 99%

“…Of the eight with the apoE2/E2 genotype, three were normolipidemic and the remaining fi ve were classifi ed with type III hyperlipidemia ( 9 ). Patient 6 was subsequently shown to be heterozygous for E2 (Arg 158 → Cys) and E2 Christchurch (Arg 136 → Ser) ( 10 ). The presence of other apoE2 mutations, including E2 Christchurch and E2 Dunedin (Arg 228 → Cys) ( 11 ), were examined and excluded in subjects with the apoE3/E2 genotype.…”

Section: Subjectsmentioning

confidence: 99%

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

Ooi

Janus

Grant

et al. 2010

Journal of Lipid Research

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Apolipoprotein (apo) E is a 34.2 kDa glycoprotein synthesized by the liver and to a lesser extent by peripheral tissues ( 1 ). It is associated in plasma with triglyceride-rich lipoproteins (TRL) and HDL particles ( 2 ). ApoE plays a central role in mediating hepatic recognition and uptake of TRL and their remnants by acting as a ligand for lipoprotein binding to the LDL receptor, LDL receptorrelated protein, and glycosaminoglycans ( 3 ). ApoE may also activate enzymes involved in lipoprotein metabolism, including hepatic lipases, cholesteryl ester transfer protein, and lecithin cholesteryl:acytransferase ( 4 ). The apoE gene is polymorphic, with three common alleles coding for three major isoforms identifi ed as E2, E3, and E4 ( 5 ).Type III hyperlipidemia, also known as dysbetalipoproteinemia, is a rare form of genetic dyslipidemia characterized by elevated plasma cholesterol and triglycerides and the presence of cholesterol-enriched remnant particles, collectively known as ␤ -VLDL ( 6 ). The accumulation of ␤ -VLDL particles may be associated with impaired TRL catabolism ( 7 ). Type III hyperlipidemic subjects may have severe xanthomatosis and signifi cantly increased risk of developing premature atherosclerosis ( 8 ). The majority of type III hyperlipidemic subjects are homozygotes for the apoE2 allele of the apoE ( APOE ) gene. However, <10% of apoE2 homozygotes develop hyperlipidemia, and most apoE2/E2 subjects are either normolipidemic or hypocholesterolemic ( 6 ). The onset of hyperlipidemia may be associated with additional genetic factors and/or environmental factors such as obesity, diabetes, and menopausal status ( 6 ). The regulation of lipoprotein transport in subjects with the apoE2/E2 genotype, in particular those withAbstract The effect of apolipoprotein (apo) E genotype on apoB-100 metabolism was examined in three normolipidemic apoE2/E2, fi ve type III hyperlipidemic apoE2/E2, and fi ve hyperlipidemic apoE3/E2 subjects using simultaneous administration of 131 I-VLDL and 125 I-LDL, and multicompartmental modeling. Compared with normolipidemic apoE2/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased plasma and VLDL cholesterol, plasma and VLDL triglycerides, and VLDL and intermediate density lipoprotein (IDL) apoB concentrations ( P < 0.05). These abnormalities were chiefl y a consequence of decreased VLDL and IDL apoB fractional catabolic rate (FCR). Compared with hyperlipidemic E3/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased IDL apoB concentration and decreased conversion of IDL to LDL particles ( P < 0.05). In a pooled analysis, VLDL cholesterol was positively associated with VLDL and IDL apoB concentrations and the proportion of VLDL apoB in the slowly turning over VLDL pool, and was negatively associated with VLDL apoB FCR after adjusting for subject group. VLDL triglyceride was positively associated with VLDL apoB concentration and VLDL and IDL apoB production rates after adjusting for subject group. A defective apoE contributes to altered lipoprotein me...

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“…Mouse and human apoE differ in 30% of their amino acid sequences with most of the differences being at the amino and carboxyl termini (1). The receptor binding domain (residues 136 -160) is highly conserved between mouse and human apoE since 21 of 25 residues are identical in this region including seven residues designated as critical for receptor binding (37,38). The residues that differ have conservative substitutions (e.g.…”

Section: Fig 5 Distribution Of Cholesterol and Apoe In Mice Fed Normentioning

confidence: 99%

Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis

Sullivan

Mezdour

Aratani

et al. 1997

Journal of Biological Chemistry

507

407

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Apolipoprotein (apo) E, a constituent of several lipoproteins, is a ligand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. We have used a gene replacement strategy to generate mice that express the human apoE3 isoform in place of the mouse protein. The levels of apoE mRNA in various tissues are virtually the same in the human apoE3 homozygous (3/3) mice and their littermates having the wild type mouse allele (؉/؉). Total cholesterol and triglyceride levels in fasted plasma from the 3/3 mice were not different from those in the ؉/؉ mice, when maintained on a normal (low fat) chow diet. We found, however, notable differences in the distribution of plasma lipoproteins and apolipoprotein E between the two groups: ␤-migrating lipoproteins and plasma apoB100 levels are decreased in the 3/3 mice, and the apoE distribution is shifted from high density lipoproteins to larger lipoprotein particles. In addition, the fractional catabolic rate of exogenously administered remnant particles without apoE was 6-fold slower in the 3/3 mice compared with the ؉/؉ mice. When the 3/3 and ؉/؉ animals were fed a high fat/high cholesterol diet, the 3/3 animals responded with a dramatic increase (5-fold) in total cholesterol compared with the ؉/؉ mice (1.5-fold), and after 12 weeks on this same diet the 3/3 animals developed significantly (at least 13-fold) larger atherosclerotic plaques in the aortic sinus area than the ؉/؉ animals. Thus the structural differences between human APOE3 and mouse ApoE proteins are sufficient to cause an increased susceptibility to dietary-induced hypercholesterolemia and atherosclerosis in the 3/3 mice.

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Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia.

Abstract: The primary structure of apolipoprotein E (apo E) was investigated in seven type III hyperlipoproteinemic patients with the apo E-2/2 phenotype. Six of the patients had identical two-dimensional tryptic peptide maps. These

Cited by 139 publications

References 54 publications

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

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

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis

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