Overview

Clinical Phenotype: Hyperlipoproteinemia Type IV, Hyperlipoproteinemia Type V
Position: (GRCh38/hg38):Chr19:44909032 C>T
Position: (GRCh37/hg19):Chr19:45412289 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918395
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in identical twin brothers from New Zealand who were obese and suffered from hyperlipoproteinemia type V (HLPP5) which converted into hyperlipoproteinemia type IV (HLPP4) after weight loss (Wardell et al., 1990). Initially, the brothers had extremely high levels of triglycerides in blood due to elevated very low-density lipoprotein (VLDL) particles which carry mainly triglycerides, and chylomicrons, particles that transport dietary lipids from the intestines and are normally only elevated after eating (Nye et al., 1986). After weight loss, chylomicron levels normalized, and their lipid profile changed to include elevations of both cholesterol and triglycerides characteristic of HLPP4.

Unexpectedly, isoelectric focusing of their ApoE protein revealed a single band corresponding to R176C (ApoE2). This result suggested the twins were APOE2 homozygotes, a genotype often tied to the presence of particles rich in cholesteryl esters, β-VLDL, which were absent from their blood, and associated with risk for a different disorder: hyperlipoproteinemia type III (HLPP3). To resolve the apparent paradox, Wardell and colleagues used two-dimensional electrophoresis and peptide sequencing which revealed the brothers carried the ApoE2 substitution in only one of their alleles (Wardell et al., 1990). The other allele appeared to be ApoE3 with an R246C substitution which caused it to migrate similarly to ApoE2 upon isoelectric focusing. Consequently, the variant was named Apolipoprotein E2-Dunedin, referring to its ApoE2-like migration and the city in which it was identified. Although DNA sequencing was not performed, the underlying change was predicted to be a point mutation, CGC to TGC, on an APOE3 backbone.

A 20-year follow-up study of the twins was published (Nye 2003), but Alzforum was unable to obtain it.

The variant was reported in the gnomAD variant database at a frequency of 0.000057, including 10 heterozygotes, five of African ancestry and five of European ancestry (gnomAD v2.1.1, Jul 2022).

Biological Effect

Based on a competitive binding assay in cultured human fibroblasts, R246C ApoE appears to bind normally to cell surface receptors for low-density lipoprotein (LDL) (Wardell et al., 1990). The assay used labeled LDL to compete against binding of total ApoE isolated from the brothers and loaded with the artificial lipid DMPC. The brothers’ ApoE performed similarly to a 1:1 mixture of wildtype ApoE3 and ApoE2.

Nonetheless, the variant may have effects on ApoE structure. A study using FRET and computational simulations to study monomeric ApoE4 suggested R246, located in the C-terminal domain, interacts with both E63 and E149 in the N-terminal domain (Stuchell-Brereton et al., 2023). These interactions were predicted to occur when the C-terminal domain is undocked from the N-terminal helix bundle, a configuration suspected to enable lipid binding. 

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, June 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. Wardell MR, Rall SC Jr, Brennan SO, Nye ER, George PM, Janus ED, Weisgraber KH. Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity. J Lipid Res. 1990 Mar;31(3):535-43. PubMed.
2. Nye ER, Sutherland WH, Janus ED. Familial type V hyperlipoproteinaemia in identical twins homozygous for apoliprotein variant E2: report. N Z Med J. 1986 Mar 12;99(797):146-9. PubMed.
3. Nye E. Twenty years of follow up of a rare lipoprotein variant (apoE2-Dunedin) in twins. N Z Med J. 2003 Aug 8;116(1179):U540. PubMed.
4. Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, Smith LG, Cubuk J, Baban B, DeKoster GT, Frieden C, Bowman GR, Soranno A. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.

Further Reading

No Available Further Reading