Overview

Clinical Phenotype: Hyperlipoproteinemia Type IIa, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908774 C>A
Position: (GRCh37/hg19):Chr19:45412031 C>A
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 AGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a Japanese man diagnosed with both severe hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, and familial hypercholesterolemia (Sakuma et al., 1995; Sakuma et al., 2014). He had elevated levels of total cholesterol and triglyceride in blood, as well as lipid deposits under the skin known as xanthomas. Moreover, as previously reported in other patients with these co-existing conditions, he had low levels of low-density lipoprotein (LDL) cholesterol.

Initially, the patient’s ApoE status was examined by isoelectric focusing revealing two species, one migrating to the position of the common R176C (ApoE2) isoform, and the other migrating to a position corresponding to a species with an additional negative charge (ApoE1). Upon DNA sequencing, the patient was found to be homozygous for the APOE2 allele and heterozygous for the R160S substitution. The variant was named ApoE1 Nagoya for the city in which it was discovered.

Of note, the proband’s mother was homozygous for APOE2 but lacked the R106S variant. Her blood lipid profile was normal and there was no known family history of cardiovascular disease. In contrast, the proband’s father and a paternal uncle suffered from hypercholesterolemia, and two paternal uncles experienced myocardial infarction. APOE genotypes were unavailable for these family members, but the authors speculated this lineage was the likely source of the R160S variant on an APOE2 background.

R160S was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Biological effect

The biological effect of this variant is unknown, but it may affect ApoE function since it is located in the receptor-binding domain, and 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). Also of note, 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, a study using FRET and computational simulations to study monomeric ApoE4 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). 

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References

Mutations Citations

1. APOE R176C (ApoE2)

Paper Citations

1. Sakuma N, Iwata S, Ikeuchi R, Ichikawa T, Hibino T, Kamiya Y, Ohte N, Kawaguchi M, Kunimatsu M, Kawahara H. Coexisting type III hyperlipoproteinemia and familial hypercholesterolemia: a case report. Metabolism. 1995 Apr;44(4):460-5. PubMed.
2. Sakuma N, Hibino T, Saeki T, Nagata T, Sato T, Okuda N, Matsunaga A, Sasaki J. Compound heterozygotes for a novel mutation, apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with severe type III hyperlipoproteinemia and familial hypercholesterolemia. J Atheroscler Thromb. 2014;21(9):983-8. Epub 2014 Jun 20 PubMed.
3. 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.
4. 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.
5. 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.
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