Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908798 C>G
Position: (GRCh37/hg19):Chr19:45412055 C>G
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 GGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a 20-year-old Japanese woman diagnosed with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Kinomura et al., 2008; Saito et al., 2020). As is typical in LPG patients, her ApoE levels in blood were elevated. Moreover, total cholesterol and triglycerides were also increased, while her levels of apolipoproteins A-I, A-II, and C-III were lower than normal. The mutation was named Okayama after the Japanese prefecture where it was discovered.

Of note, the patient was homozygous for the common APOE isoform R176C (APOE2), a risk factor for both the lipid disorder hyperlipoproteinemia type 3, and for non-LPG kidney pathology characterized by the infiltration of lipid-laden macrophages.

This variant was not reported in the gnomAD variant database (v2.1.1, Nov 2021).

Biological Effect

The biological effect of this variant is unknown, but the authors speculated its reduced negative charge may cause very low-density lipoprotein (VLDL) particles harboring the mutated protein to adhere more readily to the highly charged glomerular basement membrane of kidney capillaries (Kinomura et al., 2008).

Moreover, R168 is an evolutionarily conserved residue in the ApoE receptor-binding region (Frieden et al., 2015). It has been proposed to contribute to LDL receptor binding via its positive charge (Lund-Katz et al., 2001), which is lost in the R168G substitution. Also of note, the orientation of R168 differs between the common ApoE alleles, ApoE 2, 3, and 4 (Chen et al., 2021). In particular, ApoE2 forms a salt bridge with R168 which may contribute to ApoE2’s weak receptor binding. Thus, the effect of the R168C substitution may vary between allelic backgrounds.

Interestingly, an artificial substitution at this site, R168A, substantially reduced binding of ApoE4 to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3), a receptor that binds to ApoE4 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)

Paper Citations

1. Kinomura M, Sugiyama H, Saito T, Matsunaga A, Sada KE, Kanzaki M, Takazawa Y, Maeshima Y, Yanai H, Makino H. A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy. Nephrol Dial Transplant. 2008 Feb;23(2):751-6. Epub 2007 Nov 28 PubMed.
2. Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S, Muso E. Apolipoprotein E-related glomerular disorders. Kidney Int. 2020 Feb;97(2):279-288. Epub 2019 Nov 22 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. Lund-Katz S, Wehrli S, Zaiou M, Newhouse Y, Weisgraber KH, Phillips MC. Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE. J Lipid Res. 2001 Jun;42(6):894-901. PubMed.
5. Chen Y, Strickland MR, Soranno A, Holtzman DM. Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis. Neuron. 2021 Jan 20;109(2):205-221. Epub 2020 Nov 10 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