Identification of a new structural variant of human apolipoprotein E, E2(Lys146 leads to Gln), in a type III hyperlipoproteinemic subject with the E3/2 phenotype.
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A type III hyperlipoproteinemic subject having the apolipoprotein E (apo E) phenotype E3/2 was identified. From isoelectric focusing experiments in conjunction with cysteamine treatment (a method that measures cysteine content in apo E), the E2 isoform of this subject was determined to have only one cysteine residue, in contrast to all previously studied E2 apoproteins, which had two cysteines. This single cysteine was shown to be at residue 112, the same site at which it occurs in apo E3. From amino acid and sequence analyses, it was determined that this apo E2 differed from apo E3 by the occurrence of glutamine rather than lysine at residue 146. When phospholipid X protein recombinants of the subject's isolated E3 and E2 isoforms were tested for their ability to bind to the human fibroblast apo-B,E receptor, it was found that the E3 bound normally (compared with an apo E3 control) but that the E2 had defective binding (approximately 40% of normal). Although they contained E3 as well as E2, the beta-very low density lipoproteins (beta-VLDL) from this subject were very similar in character to the beta-VLDL from an E2/2 type III hyperlipoproteinemic subject; similar subfractions could be obtained from each subject and were shown to have a similar ability to stimulate cholesteryl ester accumulation in mouse peritoneal macrophages. The new apo E2 variant has also been detected in a second type III hyperlipoproteinemic subject.
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Certain other apoE variants are associated with a dominant mode of inheritance, i.e., heterozygosity is sufficient for expression of type III hlp.
“In contrast, certain other apoE variants are associated with a dominant mode of inheritance (5-10), i.e., heterozygosity for these apoE variants is sufficient for the expression of type III hlp.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [9]
In the Apolipoprotein E2(Lys146-Gln) discussion (page unavailable), the paper reports type III hyperlipoproteinemia in an E3/2 heterozygote. But it suggests that a separate heritable abnormality may be required to trigger the disease in that subject, so it does not establish that heterozygosity for the variant is sufficient or that inheritance is dominant. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThree apo E2 variants have been described, each differing from apo E3 by a single amino acid substitution.
“Three variants ofapo E2 have been described.Each ofthese differs from apo E3 by a single amino acid substitution (6, 12- 14).”
From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [6]
The most common apo E2 has a 158 Arg-to-Cys mutation, while 145 Arg-to-Cys and 146 Lys-to-Gln mutations have also been reported in type III hyperlipoproteinemia.
“The most common has a mutation of 158 Arg --Cys (13), but mutations of 145 Arg -* Cys (14) and 146 Lys --Gln (6) have also been reported in individuals with type III hyperlipoproteinemia.”
From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [6]
Heterozygosity for apoE2(145 Arg→Cys), apoE2(146 Lys→Gln), or apoE2-Christchurch(136 Arg→Ser) is associated with type III hyperlipoproteinemia.
“While heterozygosity for three further mutants (apoE2(145 Arg→Cys) (32, 33), apoE2(146 Lys→Gln) (34), or apoE2-Christchurch(136 Arg→Ser) (18, 33)) is associated with type III hyperlipoproteinemia, there are no family studies to ascertain whether these variants also demonstrate a dominant mode of inheritance.”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [34]
Affected subjects are often homozygous for apo E2, but heterozygosity for this variant has also been reported in association with the disease.
“Affected subjects are often homozygous for apo E2, but hetero- zygosity for this variant has also been reported in association with this disease (4)(5)(6)(7)(8).”
From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [6]
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- Authors
- Rall, S. C., Weisgraber, K. H., Innerarity, T. L., Bersot, T. P., Mahley, R. W., & Blum, C. B.
- Affiliations
- Gladstone Institutes (US)
- ORCID
- Mahley, R W
- Venue
- Journal of Clinical Investigation
- Published
- 1983-10-01
- Volume
- 72
- Issue
- 4
- Pages
- 1288-1297
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC370413
- OpenAlex
- W2074727767
- Cited by
- 141
- References
- 4
- Citations by year
- 2022: 2 · 2021: 1 · 2019: 1 · 2016: 1 · 2015: 1 · 2013: 1
- FWCI
- 22.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, structural variants, type III hyperlipoproteinemia, beta-VLDL, cholesteryl ester accumulation, macrophages
- MeSH terms
- Aged, Amino Acids, Apolipoproteins, Apolipoproteins E, Chemistry, Female, Humans, Hyperlipoproteinemia Type III, Isoelectric Focusing, Lipoproteins, VLDL, Male, Middle Aged, Phenotype, Receptors, Cell Surface, Genetic Variation, Low Density Lipoprotein Receptor-Related Protein-1, Apolipoprotein E2, Chemical Phenomena
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