Overview

Clinical Phenotype: Alzheimer's Disease, Blood Lipids/Lipoproteins, Cardiovascular Disease
Position: (GRCh38/hg38):Chr19:44908667 C>T
Position: (GRCh37/hg19):Chr19:45411924 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs937063425
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This rare variant was found in a randomly selected cohort of 346 healthy, unrelated Swiss volunteers from the Basel Study on the Elderly (BASEL) (Miserez et al., 2003). It was absent from 5,500 individuals in the general Swiss population, as well as from the gnomAD variant database.

In the proband, whose was clinically monitored from age 50 to 85, elevated plasma triglyceride levels and premature, slowly progressing coronary artery disease were observed starting at age 55. He was a carrier of the common APOE2 and APOE3 alleles. In addition, two other carriers in the family had slightly elevated cholesterol levels compared with non-carrier family members from the same generation who were matched for age and gender. Additional signs of potentially increased risk of atherosclerosis in these individuals included a higher ratio of triglycerides in very low-density lipoprotein (VLDL) to cholesterol in VLDL, and a higher ratio of cholesterol in low-density lipoprotein (LDL) to ApoB-100. These carriers had APOE3/APOE3 and APOE3/APOE4 genetic backgrounds.

Of note, one of the family members of the proband was an 80-year-old man with Alzheimer’s disease (AD). Although the man was not genotyped directly, his carrier status was inferred from the genotypes of his brother and daughter who were both carriers. No other information on the relationship of this variant to AD is available. Biological Function Despite the mutant’s apparent effects on carriers’ blood lipid profiles, the binding affinities of this variant for LDL receptors and heparin in vitro were reported as similar to those of control ApoE3 protein (Miserez et al., 2003). Receptor binding was tested using recombinant A124V bound to dimyristoylphosphatidylcholine (DMPC) to model the lipidated, biologically active protein in a competitive binding assay using labeled LDL and human skin fibroblasts. To more closely mimic in vivo conditions, recombinant proteins were also loaded onto VLDL particles isolated from an individual deficient in ApoE. Consistent with the initial results, receptor binding, internalization, and degradation were similar to those of control ApoE3-loaded particles. Also, heparin affinity appeared unaffected as revealed by binding of DMPC-loaded vesicles, containing either mutant or control ApoE3, to heparin-coated beads.

The authors speculated the variant might instead affect the ApoE-dependent regulation of lipoprotein lipase, an enzyme on the surface of vascular endothelial cells that degrades circulating triglycerides in VLDL particles.

Although the variant does not affect the net charge of the ApoE protein, it is expected to distort the structure of the third β-helix in the N-terminal domain. Moreover, the authors noted the position is highly conserved between mammalian species, and the variant is near APOE4, a known modifier of ApoE structure and function. However, the variant’s PHRED-scaled CADD score, which integrates diverse information in silico was 17.8, below the commonly used threshold of 20 used to predict deleteriousness (CADD v.1.6, May 2022).

Nomenclature Notes

The protein variant was named ApoE3 Basel because it migrates similarly to ApoE3 upon isoelectric focusing and was discovered in a volunteer from the BASEL cohort.

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE C130R (ApoE4)

Paper Citations

1. Miserez AR, Scharnagl H, Muller PY, Mirsaidi R, Stähelin HB, Monsch A, März W, Hoffmann MM. Apolipoprotein E3Basel: new insights into a highly conserved protein region. Eur J Clin Invest. 2003 Aug;33(8):677-85. PubMed.

Further Reading

No Available Further Reading