Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908799 G>C
Position: (GRCh37/hg19):Chr19:45412056 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 mutation was identified in a Chinese family spanning three generations who suffered from lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Luo et al., 2008; Saito et al., 2020).

The variant was identified by sequencing exon 4 of APOE and found in all four members diagnosed with LPG, as well as in one of seven asymptomatic individuals (Luo et al., 2008). Of note, the asymptomatic carrier was only 21 years old, and a renal biopsy was not collected. All carriers were heterozygotes. The clinical symptoms were first noted in the mother at age 62, in her daughter and son at age 40, and in her granddaughter at age 12.

Carriers of the mutation had significantly higher levels of plasma triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, and ApoE, but lower levels of low-density lipoprotein (LDL) cholesterol compared with family non-carriers. These abnormalities were observed even though all LPG patients were taking lipid-lowering medications at the time of sample collection. There was no detectable difference in plasma levels of ApoA1 and ApoB between carriers and family non-carriers, but the carriers had lower ApoB levels compared with healthy subjects. Interestingly, family non-carriers had higher levels of both total- and LDL-cholesterol compared with healthy subjects, suggesting some degree of abnormal lipid metabolism even in the absence of the mutation. The variant was named ApoE Guangzhou after the city where the study was done.

This variant is absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Biological Effect

The biological effect of this mutation is unknown, but 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 substituted with a hydrophobic residue in R168P. In addition, noting that prolines are helix breakers in globular proteins, Luo and co-workers speculated the substitution may change protein structure (Luo et al., 2008). 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 R168P 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).

There are three additional mutations at this site, two of which have been also tied to LPG. Also of note, R168P’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

Paper Citations

1. Luo B, Huang F, Liu Q, Li X, Chen W, Zhou SF, Yu X. Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol. 2008;28(2):347-53. Epub 2007 Nov 29 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