Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Cardiovascular Disease
Reference Assembly: GRCh37/hg19
Position: Chr19:45411848 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1180612218
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAA to AAA
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 43-year-old German man with moderate hypercholesterolemia and elevated levels of low-density lipoprotein (LDL) in blood (Ruzicka et al., 1993). Although he had hypertension, he had no signs of coronary or peripheral atherosclerosis, nor did he have a family history of blood lipid abnormalities or cardiovascular disease.

Upon isoelectric focusing and immunoblotting of the patient’s delipidated plasma proteins, the authors identified two ApoE bands, one with an isoelectric point corresponding to the common ApoE3 allele and the other with two additional net positive charges, ApoE5. The new species was thus named ApoE5 Frankfurt, after the city where it was discovered. Further analyses, including DNA sequencing, revealed the underlying alteration: a Q99K substitution present in the common C130R (APOE4) link isoform.

A single heterozygote carrier of European ancestry was reported in the gnomAD variant database (gnomAD v2.1.1, Apr 2022). Biological effect The biological effect of this variant is unknown. Preliminary, unpublished findings by the authors indicated the patient’s very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) bound to cell surface receptors on human skin fibroblasts more effectively than those from either APOE3 homozygotes or APOE3/4 heterozygotes (Ruzicka et al., 1993). However, whether this alteration is due to increased binding activity or to elevated ApoE content in the lipoprotein particles remains uncertain.

Q99 is outside the receptor binding domain but, as noted by Ruzicka and colleagues, the addition of a positive charge at this site—in N-terminal helix 2, apposed to the loop connecting it to helix 3—may substantially affect the protein’s conformation. Indeed, a study using FRET and computational simulations to study monomeric ApoE4 predicted interactions between Q99 and amino acids in helix 4, Q181 and G183. These interactions were predicted to occur when the C-terminal domain of ApoE is undocked from the N-terminal helix bundle, a configuration suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

This variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was close to 20, a commonly used threshold to predict deleteriousness, but at 18.99, it fell short of this mark (CADD v.1.6, Apr 2022).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Ruzicka V, März W, Russ A, Fisher E, Mondorf W, Gross W. Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis. Electrophoresis. 1993 Oct;14(10):1032-7. PubMed.
2. 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