Overview

Clinical Phenotype: Hyperlipoproteinemia Type III
Reference Assembly: GRCh37/hg19
Position: Chr19:45412046 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs1402219759
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 53-year-old Spanish individual with combined hyperlipidemia (Bea et al., 2023). The variant was identified by targeted sequencing of APOE exon 4. Hyperlipidemia was diagnosed based on elevated levels of triglycerides (TG) and cholesterol other than that in high-density lipoprotein (non-HDLc) or ApoB (TG≥150mg/dL and non-HDLc ≥160 mg/dL or ApoB≥120 mg/dL). The carrier met the criteria for dysbetalipoproteinemia (non-HDLc/ApoB≥1.7 and TG/ApoB≥1.35), also known as hyperlipoproteinemia type 3 (HLPP3) and had high levels of very low-density lipoprotein cholesterol (VLDLc), and high ratios of VLDLc/VLDL-TG and VLDLc/ApoB. Although HLPP3 is often associated with atherosclerotic cardiovascular disease, this condition was not diagnosed at the time of the study. The carrier had an APOE3/E4 genotype.

Of note, this substitution was also identified together with K164N (K164_R165delinsNW) in a woman with HLPP3 (Hoffer et al., 1996).

The variant was absent from both the gnomAD variant database and the 1000 Genomes Project.

Biological Effect

This substitution localizes to the receptor-binding region of ApoE. The mutant protein appeared to have reduced affinity for low-density lipoprotein (LDL) receptors compared with wildtype ApoE3, although the affinity was higher than that of ApoE2 (Bea et al., 2023).  Affinity was assessed by in vitro binding assays using the LDL receptor ectodomain attached to plates exposed to VLDL particles isolated from the patient.

Of note, R165W may also affect binding to other cell surface receptors. Substituting adenine at R165 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, R165W may also alter ApoE’s main heparin-binding site since R165 appears to be a key residue for ApoE's interaction with the sulfo groups of heparan sulfate proteoglycans (HSPGs) in ApoE’s main heparin-binding site (Libeu et al., 2001; Saito et al., 2003; Mah et al., 2023).

R165 is highly conserved (Frieden et al., 2015) and at least three of four in silico algorithms predicted it is deleterious (Bea et al., 2023).   Consistent with these observations, its PHRED-scaled CADD score (32), which integrates diverse information in silico, was above 20, a commonly used threshold to predict deleteriousness.

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References

Mutations Citations

1. APOE K164_R165delinsNW

Paper Citations

1. Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C, Cenarro A. Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol. 2023 Jun;43(6):1066-1077. Epub 2023 Apr 13 PubMed.
2. Hoffer MJ, Niththyananthan S, Naoumova RP, Kibirige MS, Frants RR, Havekes LM, Thompson GR. Apolipoprotein E1-Hammersmith (Lys146-->Asn;Arg147-->Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia. Atherosclerosis. 1996 Aug 2;124(2):183-9. 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. Saito H, Dhanasekaran P, Nguyen D, Baldwin F, Weisgraber KH, Wehrli S, Phillips MC, Lund-Katz S. Characterization of the heparin binding sites in human apolipoprotein E. J Biol Chem. 2003 Apr 25;278(17):14782-7. Epub 2003 Feb 14 PubMed.
6. Mah D, Zhu Y, Su G, Zhao J, Canning A, Gibson J, Song X, Stancanelli E, Xu Y, Zhang F, Linhardt RJ, Liu J, Wang L, Wang C. Apolipoprotein E Recognizes Alzheimer's Disease Associated 3-O Sulfation of Heparan Sulfate. Angew Chem Int Ed Engl. 2023 Jun 5;62(23):e202212636. Epub 2023 Apr 28 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