Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44907807 G>A
Position: (GRCh37/hg19):Chr19:45411064 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs201672011
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to AAG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant was examined in a study of dementia, including Alzheimer’s disease (AD), but its association with the disorder remains unclear (Rasmussen et al., 2020). In two cohorts totaling more than 100,000 individuals from Copenhagen, Denmark, the variant was found in eight individuals, two who were at least 60 years old, one of whom had AD. 

E31K was first identified in two French-Canadian individuals (Mailly et al., 1991). One was a 41-year-old man with a normal blood lipid profile, but a family history of cerebrovascular problems and brain tumors. The variant was detected by isoelectric focusing of the very-low-density lipoprotein (VLDL) fraction of his blood, which revealed a band migrating to a more basic position than the common C130R (APOE4) allele. Accordingly, it was named ApoE5. The band was present in the proband’s two sisters, his son, and one uncle, but absent from other family members spanning three generations, indicating Mendelian transmission. All carriers had normal lipid levels in blood and were positive for the reference ApoE3 allele.

In the same study, the ApoE5 band was also detected in an apparently unrelated 52-year-old woman with elevated cholesterol and triglyceride levels who suffered from angina, chest pain caused by reduced blood flow to the heart. The band was absent from her husband’s and daughter’s blood. Although the two probands were thought to be unrelated, preliminary studies of DNA polymorphisms in their APOE-C-I-C-II gene cluster suggest they may share common ancestry.

Epitope-specific antibodies to ApoE revealed a disruption of antibody binding to the N-terminus of the protein, prompting the authors to sequence the DNA coding for this region using exon 3 primers for PCR amplification. This revealed a G>A point mutation giving rise to the E31K substitution. Of note, E31K displays anomalous migration on SDS-polyacrylamide gel electrophoresis. It migrates as if it were 1-2 KDa smaller than wild-type ApoE.

In eight Danish carriers, plasma levels of several lipid species, including cholesterol in low-density lipoprotein particles (LDL-C), cholesterol in high-density lipoprotein particles (HDL-C), remnant cholesterol, and triglycerides, were similar to non-carrier levels, as were ApoE levels (Rasmussen et al., 2020, Rasmussen et al., 2023). 

In one family, this variant was found together with the R163C variant. All seven reported carriers of the compound mutation, referred to as ApoE4 Philadelphia based on its migration on an isoelectric focusing gel, had altered blood lipid profiles. The original proband, a 24-year-old homozygous female, suffered from hyperlipoproteinemia type III (HLPP3), a condition characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease (Lohse et al., 1991; Lohse et al., 1992). The other six carriers, on the other hand, were heterozygotes, having only a moderate form of HLPP3, lacking clinical symptoms. The authors concluded the compound mutant exhibits incomplete dominance for HLPP3. Another compound variant, E31K/R269G, was identified in an APOE3/E4 heterozygote, but no further information for this carrier was provided (Rasmussen et al., 2023). 

The frequency of E31K in the gnomAD variant database was 0.00013, including 37 heterozygote carriers (v2.1.1, Apr 2022). Although of various ancestries, the most common was Latino/Admixed American, including 12 carriers.

Biological Effect

The biological effect of this variant is unknown. It is in a region hypothesized to affect heparin binding to a secondary heparin-binding site in the carboxy-terminus of ApoE (Weisgraber et al., 1986).

Although its PHRED-scaled CADD score, which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Apr 2022), several supervised-learning algorithms predicted it is deleterious (Pires et al., 2017, see supplementary table 2).

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References

Mutations Citations

1. APOE R163C
2. APOE R269G

Paper Citations

1. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement. 2020 Dec;16(12):1624-1637. Epub 2020 Aug 18 PubMed.
2. Mailly F, Xu CF, Xhignesse M, Lussier-Cacan S, Talmud PJ, Davignon J, Humphries SE, Nestruck AC. Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects. J Lipid Res. 1991 Apr;32(4):613-20. PubMed.
3. Rasmussen KL, Luo J, Nordestgaard BG, Tybjærg-Hansen A, Frikke-Schmidt R. APOE and vascular disease: Sequencing and genotyping in general population cohorts. Atherosclerosis. 2023 Nov;385:117218. Epub 2023 Aug 9 PubMed.
4. Lohse P, Mann WA, Stein EA, Brewer HB Jr. Apolipoprotein E-4Philadelphia (Glu13----Lys,Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem. 1991 Jun 5;266(16):10479-84. PubMed.
5. Lohse P, Rader DJ, Brewer HB Jr. Heterozygosity for apolipoprotein E-4Philadelphia(Glu13----Lys, Arg145----Cys) is associated with incomplete dominance of type III hyperlipoproteinemia. J Biol Chem. 1992 Jul 5;267(19):13642-6. PubMed.
6. Weisgraber KH, Rall SC Jr, Mahley RW, Milne RW, Marcel YL, Sparrow JT. Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J Biol Chem. 1986 Feb 15;261(5):2068-76. PubMed.
7. Pires AS, Porto WF, Franco OL, Alencar SA. In silico analyses of deleterious missense SNPs of human apolipoprotein E3. Sci Rep. 2017 May 30;7(1):2509. PubMed.

Further Reading

No Available Further Reading