A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1
Open accessAbstract
A new apolipoprotein E (apo E) phenotype has been demonstrated in a Finnish hypertriglyceridemic subject (R.M.). At the time of this study, R.M.'s plasma triglyceride and cholesterol levels were 1,021 and 230 mg/dl, respectively. The subject's apo E isoelectric focusing pattern was characterized by two major bands, one in the E3 position and the other in the E1 position. Normally the E1 position is occupied by sialylated derivatives of apo E4, E3, or E2. The E1 band of subject R.M. is not a sialylated form, however, because it was not affected by neuraminidase digestion. The identity of the E1 variant as a genetically determined structure was established by amino acid and partial sequence analyses, confirming that the variant is an example of a previously uncharacterized apo E phenotype, E3/1. Both cysteamine modification and amino acid analysis demonstrated that this variant contains two cysteine residues per mole. Sequence analysis of two cyanogen bromide fragments and one tryptic fragment of the apo E3/1 showed that it differs from E2(Arg158----Cys) at residue 127, where an aspartic acid residue is substituted for glycine. This single amino acid interchange is sufficient to account for the one-charge difference observed on isoelectric focusing gels between E2(Arg158----Cys) and the E1 variant. The variant has been designated E1 (Gly127----Asp, Arg158----Cys). When compared with apo E3, the E1 variant demonstrated reduced ability to compete with 125I-LDL for binding to LDL (apo B,E) receptors on cultured fibroblasts (approximately 4% of the amount of binding of apo E3). This defective binding is similar to that of E2-(Arg158----Cys). Therefore, the binding defect of the variant is probably due to the presence of cysteine at residue 158, rather than aspartic acid at residue 127. In contrast, the apo E3 isoform from this subject demonstrated normal binding activity, indicating that it has a normal structure. In family studies, the vertical transmission of the apo E1 variant has been established. It is not yet clear, however, if the hypertriglyceridemia observed in the proband is associated with the presence of the E1(Gly127----Asp, Arg158----Cys) variant.
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Based on previous research, the ε2ε1 genotype is considered likely pathogenic for FD.
“Based on previous research data [32,33,34,35,36], we considered the ε2ε1 genotype as likely pathogenic for FD.”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [32]
The Introduction (page unavailable) links familial dysbetalipoproteinemia to apo E2, and the paper reports defective receptor binding by the E1 variant. The Discussion (page unavailable) mentions an E2/1 phenotype identified by other researchers, but this study characterizes an E3/1 subject and does not assess whether ε2ε1 is likely pathogenic for familial dysbetalipoproteinemia. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys).
“The Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys)26, 38, 56, 57).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [56]
The Discussion identifies APOE1 as carrying both Gly127Asp and Arg158Cys and says it probably arose by mutation of an APOE2 allele. The paper establishes their coexistence in the observed variant, but does not establish population-level linkage disequilibrium. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThree carriers of the rare p.Gly145Asp variant had the ε2ε2 genotype, forming the rare ε2ε1 genotype.
“In our study, three carriers of the rare p.Gly145Asp variant had the ε2ε2 (homozygous for the common p.Arg176Cys variant), forming the rare ε2ε1 genotype [32,33,34,35,36].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [32]
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Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
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- Authors
- Weisgraber, K. H., Rall, S. C., Innerarity, T. L., Mahley, R. W., Kuusi, T., & Ehnholm, C.
- Affiliations
- University of California, San Francisco (US)
- ORCID
- Mahley, R W
- Venue
- Journal of Clinical Investigation
- Published
- 1984-04-01
- Volume
- 73
- Issue
- 4
- Pages
- 1024-1033
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC425115
- OpenAlex
- W2063987466
- Cited by
- 111
- References
- 6
- Citations by year
- 2025: 4 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2019: 3 · 2016: 2 · 2015: 1 · 2013: 1 · 2012: 2
- FWCI
- 11.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- hypertriglyceridemia, LDL receptor binding, sialylation, vertical transmission, familial hypertriglyceridemia, amino acid substitutions, isoelectric focusing
- MeSH terms
- Adolescent, Amino Acid Sequence, Amino Acids, Apolipoproteins, Apolipoproteins E, Child, Cysteamine, Female, Humans, Hyperlipoproteinemia Type IV, Isoelectric Focusing, Male, Middle Aged, Phenotype, Receptors, Cell Surface, Receptors, LDL, Genetic Variation
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