Overview

Clinical Phenotype: Splenomegaly
Reference Assembly: GRCh37/hg19
Position: Chr19:45411947 C>T
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 TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was found in an 18-year-old Japanese woman with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Hagiwara et al., 2008). She also had an enlarged spleen. Her serum levels of lipids and lipoproteins, including ApoE, were initially in the normal range, but subsequently, triglycerides and high-density lipoprotein (HDL) cholesterol substantially increased.

Isoelectric focusing and immunoblotting of ApoE proteins revealed the proband, her sister, and her mother had ApoE alleles that migrated to the ApoE3 and ApoE2 positions, while her father and brother had only the ApoE3-migrating allele. Upon DNA sequence analysis, the ApoE2-migrating species was found to correspond to R132C, rather than to the common R176C (APOE2) allele, with all family members having an APOE3/3 genotype.

Although there was no known family history of renal or lipid metabolism disease, the proband’s mother, a mutation carrier, had an enlarged spleen. Of note, this condition has also been reported in some carriers of L167del.

R132C is found in the gnomAD variant database at a frequency of 0.00001011 with only two allele counts. It is absent from the gnomAD non-neuro subdivision.

Biological Effect

This variant has been shown to be aggregation-prone as assessed by dynamic light-scattering and by measurements of its binding to the amyloid probe thioflavin T (Katsarou et al., 2018). It was reported to reduce helical content and cause thermodynamic destabilization predicted to induce protein misfolding.

Moreover, R132 is highly conserved. Its location in N-terminal helix 3 may affect the conformation of helix 4 which harbors ApoE’s receptor-binding region (Frieden, 2015). Also, 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).

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).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE L167del
3. APOE C130R (ApoE4)

Paper Citations

1. Hagiwara M, Yamagata K, Matsunaga T, Arakawa Y, Usui J, Shimizu Y, Aita K, Nagata M, Koyama A, Zhang B, Mastunaga A, Saku K, Saito T. A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy. Nephrol Dial Transplant. 2008 Jan;23(1):381-4. Epub 2007 Oct 28 PubMed.
2. Katsarou M, Stratikos E, Chroni A. Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy. J Lipid Res. 2018 Dec;59(12):2339-2348. Epub 2018 Oct 11 PubMed.
3. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 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. 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.
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. 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