Overview

Position: (GRCh38/hg38):Chr19:44908690 C>A
Position: (GRCh37/hg19):Chr19:45411947 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs11542041
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 has not been associated with any disease or condition, but computer modeling suggests it alters ApoE structure and function substantially. It was initially sequenced in the 1000 Genomes Project and subsequent studies identified it as likely to be damaging (Namboori et al., 2011; Masoodi et al., 2012; Pires et al., 2017). The substitution results in a non-conservative amino acid change, from nonpolar charged to polar uncharged, in an evolutionarily conserved residue.

In an analysis of 31 APOE genetic variants using 16 in silico prediction tools, R132S was classified as “convergent deleterious” (Pires et al., 2017). To qualify for this classification, variants had to receive deleterious predictions from at least three algorithms in each of four categories: sequence homology, supervised-learning, protein-sequence and structure, and consensus-based methods. Furthermore, molecular dynamics simulations predicted the R132S substitution results in a loss of two hydrogen bonds between the ApoE N- and C-terminal domains which could lead to the separation of the two domains, exposing the receptor binding site, an event that normally occurs only after lipid binding. Of note, predicted interactions between the N- and C-terminals of ApoE vary between studies, depending on the ApoE constructs used and the methods applied. For example, while an NMR study of an ApoE3-like construct predicted R132 forms a salt bridge with glutamate 256 (Chen et al., 2011), a 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).

This 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).

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Mutations Citations

1. APOE C130R (ApoE4)

Paper Citations

1. Namboori PK, Vineeth KV, Rohith V, Hassan I, Sekhar L, Sekhar A, Nidheesh M. The ApoE gene of Alzheimer's disease (AD). Funct Integr Genomics. 2011 Dec;11(4):519-22. Epub 2011 Jul 19 PubMed.
2. Masoodi TA, Al Shammari SA, Al-Muammar MN, Alhamdan AA. Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer's Disease. Neurol Res Int. 2012;2012:480609. Epub 2012 Mar 13 PubMed.
3. Pires AS, Porto WF, Franco OL, Alencar SA. In silico analyses of deleterious missense SNPs of human apolipoprotein E3. Sci Rep. 2017 May 30;7(1):2509. PubMed.
4. 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.
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