Overview

Clinical Phenotype: Blood Lipids/Lipoproteins
Reference Assembly: GRCh37/hg19
Position: Chr19:45412493 A>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs28931579
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGC to CGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This rare variant was identified in a healthy, 40-year-old Dutch man (van den Maagdenberg et al., 1993). Analysis of the carrier’s ApoE proteins by isoelectric focusing showed a species that migrated slightly more towards the anode than the common ApoE isoform C130R (ApoE4), in addition to one at the ApoE3 position.  DNA sequencing revealed the subject had a homozygous APOE3 genotype with an arginine substitution at serine 314. The proband’s father and brother also carried the S314R variant. Total cholesterol and triglyceride levels in blood were within the normal range in all carriers at ages 36, 40, and 69.

The global frequency of this variant in the gnomAD variant database is 0.000091, with a higher frequency of 0.00037 in the South Asian population (gnomAD v2.1.1, Sep 2022).

Biological Effect

The biological effect of this variant is unknown, but serine 314 is an O-glycosylation and phosphorylation site (see Martens et al., 2022), and ApoE in cerebrospinal fluid is abundantly glycosylated at its C-terminus, roughly 10-fold more than in plasma (Flowers et al., 2020; Hu et al., 2020). This modification is suspected to protect against self-association and potentially affect the function of the lipid-binding region (Lee et al., 2010). Moreover, ApoE glycosylation varies between cell types, ApoE isoforms, and cellular versus secreted forms, and may play a role in modulating neuroinflammation (Lanfranco et al., 2021).

As noted in the gnomAD database, in silico algorithms predicted this substitution is benign (Polyphen) and tolerated “with low confidence” (SIFT) (gnomAD v2.1.1, Sep 2022). Moreover, its PHRED-scaled CADD score (10.89), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Nov 2022).

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References

Paper Citations

1. van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van't Hooft FM, Assmann G, Hofker MH. Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet. 1993 May;52(5):937-46. PubMed.
2. Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, Holtzman DM, Bu G. ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron. 2022 Apr 20;110(8):1304-1317. Epub 2022 Mar 16 PubMed.
3. Flowers SA, Grant OC, Woods RJ, Rebeck GW. O-glycosylation on cerebrospinal fluid and plasma apolipoprotein E differs in the lipid-binding domain. Glycobiology. 2020 Jan 28;30(2):74-85. PubMed.
4. Hu Y, Meuret C, Go S, Yassine HN, Nedelkov D. Simple and Fast Assay for Apolipoprotein E Phenotyping and Glycotyping: Discovering Isoform-Specific Glycosylation in Plasma and Cerebrospinal Fluid. J Alzheimers Dis. 2020;76(3):883-893. PubMed.
5. Lee Y, Kockx M, Raftery MJ, Jessup W, Griffith R, Kritharides L. Glycosylation and sialylation of macrophage-derived human apolipoprotein E analyzed by SDS-PAGE and mass spectrometry: evidence for a novel site of glycosylation on Ser290. Mol Cell Proteomics. 2010 Sep;9(9):1968-81. Epub 2010 May 28 PubMed.
6. Lanfranco MF, Sepulveda J, Kopetsky G, Rebeck GW. Expression and secretion of apoE isoforms in astrocytes and microglia during inflammation. Glia. 2021 Jun;69(6):1478-1493. Epub 2021 Feb 8 PubMed.

Further Reading

No Available Further Reading