Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Position: (GRCh38/hg38):Chr19:44908784 G>A
Position: (GRCh37/hg19):Chr19:45412041 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918397
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to CAT
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant, sequenced only at the protein level, was identified in a 29-year-old Japanese man with hyperlipoproteinemia (Suehiro et al.1990). He had increased levels of very low-density lipoprotein (VLDL) cholesterol, with a corresponding electrophoretic species known as “broad-beta band”, and decreased levels of low-density lipoprotein (LDL) in serum. These alterations are typical of hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, a condition that often results in early onset atherosclerosis and heart disease. However, the patient’s cholesterol to triglyceride ratio in VLDL particles was lower than expected for HLPP3.

The patient’s mother and maternal grandmother expressed he same altered protein and suffered from a similar condition. However, an uncle, who also had the altered protein, did not have hyperlipoproteinemia.

A single heterozygote carrier of East Asian ancestry was reported in the gnomAD variant database (v2.1.1, May 2022).

Biological Effect

The biological effect of this variant is unknown, but R163 is in the receptor-binding region of ApoE and has been reported to play a critical role in heparin binding (Weisgraber et al., 1986; Libeu et al., 2001; Dong et al., 2001). Moreover, R163 has been predicted to engage in several long-range interactions that may be important to ApoE's' 3D structure. An NMR study of an ApoE3-like construct harboring five mutations to keep it from aggregating, suggested R163 interacts with Q59 (Chen et al., 2011). In addition, a study using FRET and computational simulations to analyze monomeric ApoE4, predicted interactions with E27 and E45 when the C-terminal domain is undocked from the N-terminal helix bundle, a form suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

R163 may also play a role in the formation of ApoE dimers which adopt different conformations in an isoform-dependent manner (Nemergut et al., 2023). Interestingly, a metabolite of the AD drug candidate ALZ-801 was observed to interact with several amino acids involved in dimerization, including R163, possibly decreasing the stability of ApoE4 V-shaped dimers.

The 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).

Nomenclature Notes

The variant was named ApoE Kochi, after the city where it was identified.

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References

Therapeutics Citations

1. ALZ-801

Paper Citations

1. Suehiro T, Yoshida K, Yamano T, Ohno F. Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi). Jpn J Med. 1990 Nov-Dec;29(6):587-94. PubMed.
2. Weisgraber KH, Rall SC Jr, Mahley RW, Milne RW, Marcel YL, Sparrow JT. Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J Biol Chem. 1986 Feb 15;261(5):2068-76. 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. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8. Epub 2011 Aug 22 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. Nemergut M, Marques SM, Uhrik L, Vanova T, Nezvedova M, Gadara DC, Jha D, Tulis J, Novakova V, Planas-Iglesias J, Kunka A, Legrand A, Hribkova H, Pospisilova V, Sedmik J, Raska J, Prokop Z, Damborsky J, Bohaciakova D, Spacil Z, Hernychova L, Bednar D, Marek M. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate. Mol Neurodegener. 2023 Jun 6;18(1):38. PubMed.

Further Reading

No Available Further Reading