Overview

Clinical Phenotype: Cardiovascular Disease, Diabetes Mellitus
Position: (GRCh38/hg38):Chr19:44908691 G>C
Position: (GRCh37/hg19):Chr19:45411948 G>C
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 CCC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a U.K. study of 765 individuals with type 2 diabetes (Stephens et al, 2005). The proband was a 70-year-old Caucasian man who had suffered from diabetes for 18 years. He had elevated cholesterol and moderately decreased ApoE levels in plasma. He also had coronary heart disease, which affected a first-degree relative as well.

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

Biological Effect

The biological effect of this mutation is unknown, but R132 is highly conserved (Frieden, 2015) and Stephens and colleagues predicted the substitution of a hydrophilic positively charged, polar amino acid with a hydrophobic, nonpolar amino acid might affect receptor binding (Stephens et al, 2005). R132 resides in N-terminal helix 3 and may affect the conformation of helix 4 which harbors ApoE’s receptor-binding region. Moreover, R132 is predicted to form a salt bridge with glutamate 256, bringing together ApoE’s N- and C-termini (Chen et al., 2011). In the presence of lipids, this putative bridge may be broken as part of the conformational change associated with lipid binding (Prakashchand and Mondal, 2021). Note, however, that the R132-E256 prediction was based on an NMR study of an ApoE3-like construct harboring multiple mutations to keep it from aggregating (Chen et al., 2011). A subsequent study using FRET and computational simulations to study monomeric ApoE4 did not identify this interaction (Stuchell-Brereton et al., 2023).

Interestingly, the artificial R132A substitution nearly abolished binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 much more strongly than to ApoE3 or ApoE2, and activates pro-inflammatory pathways (Zhou et al., 2023).

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).

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References

Mutations Citations

1. APOE C130R (ApoE4)

Paper Citations

1. Stephens JW, Sozen MM, Whittall RA, Caslake MJ, Bedford D, Acharya J, Hurel SJ, Humphries SE. Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem. 2005 Jan;51(1):119-24. Epub 2004 Oct 28 PubMed.
2. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
3. 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.
4. Prakashchand DD, Mondal J. Conformational Reorganization of Apolipoprotein E Triggered by Phospholipid Assembly. J Phys Chem B. 2021 May 27;125(20):5285-5295. Epub 2021 May 12 PubMed.
5. 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.
6. 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.

Further Reading

No Available Further Reading