Overview

Clinical Phenotype: Cardiovascular Disease, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908775 G>T
Position: (GRCh37/hg19):Chr19:45412032 G>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CTC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a Caucasian French man and his father, both diagnosed with hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia (Richard et al., 1994; Richard et al., 1995). This condition is characterized by elevated levels of cholesterol, triglycerides, and very low-density lipoprotein (VLDL) cholesterol which can lead to coronary and peripheral vascular disease. At age 51, the proband had no vascular disease symptoms, but his father, age 75, had atherosclerosis and lipid deposits, known as xanthomas, under his skin.

The proband’s ApoE protein was initially analyzed by isoelectric focusing and 2D electrophoresis, revealing two species: one corresponding to the common ApoE3 isoform, and another similar to the ApoE2 isoform, but more acidic and with a lower molecular weight. DNA sequence analysis showed that this second species corresponded to the R160L mutation on an APOE2 backbone. The father carried the same mutation in heterozygous form and was homozygous for the APOE2 allele. Because APOE2 homozygosity is a common cause of HLPP3, the authors noted that the father’s severe HLPP3 might have resulted from the combined effects of this homozygosity and the presence of the R160L variant.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Biological Effect

The biological effect of this variant is unknown, but the authors suspected a damaging effect since it is located in the ApoE receptor-binding domain (Richard et al., 1995). Interestingly, an artificial substitution at this same site, R160A, substantially reduced binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 more strongly than to ApoE3 or ApoE2 and activates pro-inflammatory pathways (Zhou et al., 2023). Moreover, biochemical examinations of ApoE-heparin binding have pinpointed R160 as a critical amino acid for this interaction (Libeu et al., 2001; Dong et al., 2001).

Substitution of R160 may also have conformational consequences. A study using FRET and computational simulations to analyze monomeric ApoE4, for examaple, predicted R160 contacts D245 in the C-terminal domain, when this domain is undocked from the N-terminal helix bundle (Stuchell-Brereton et al., 2023).

R160 is evolutionarily conserved across 63 mammalian species (Frieden et al., 2015). This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022).

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References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. Richard P, Thomas G, de Zulueta MP, De Gennes JL, Thomas M, Cassaigne A, Béréziat G, Iron A. Common and rare genotypes of human apolipoprotein E determined by specific restriction profiles of polymerase chain reaction-amplified DNA. Clin Chem. 1994 Jan;40(1):24-9. PubMed.
2. Richard P, de Zulueta MP, Beucler I, De Gennes JL, Cassaigne A, Iron A. Identification of a new apolipoprotein E variant (E2 Arg142-->Leu) in type III hyperlipidemia. Atherosclerosis. 1995 Jan 6;112(1):19-28. PubMed.
3. Zhou J, Wang Y, Huang G, Yang M, Zhu Y, Jin C, Jing D, Ji K, Shi Y. LilrB3 is a putative cell surface receptor of APOE4. Cell Res. 2023 Feb;33(2):116-130. Epub 2023 Jan 2 PubMed.
4. Libeu CP, Lund-Katz S, Phillips MC, Wehrli S, Hernáiz MJ, Capila I, Linhardt RJ, Raffaï RL, Newhouse YM, Zhou F, Weisgraber KH. New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J Biol Chem. 2001 Oct 19;276(42):39138-44. Epub 2001 Aug 10 PubMed.
5. Dong J, Peters-Libeu CA, Weisgraber KH, Segelke BW, Rupp B, Capila I, Hernáiz MJ, LeBrun LA, Linhardt RJ. Interaction of the N-terminal domain of apolipoprotein E4 with heparin. Biochemistry. 2001 Mar 6;40(9):2826-34. PubMed.
6. 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.
7. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.

Further Reading

No Available Further Reading