Overview

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

Findings

This variant has been described in three individuals, two diagnosed with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Saito et al., 2020).

R168C was first identified in a middle-aged Italian woman with LPG and elevated levels of total cholesterol, triglycerides, and ApoE in plasma (Russi et al., 2009; Magistroni et al., 2013). 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.

The mutation, identified by sequencing of exon 4 of APOE, was absent from 150 controls and from six family members. It was named Modena for the city in which the proband lived. The non-carrier family members had normal levels of cholesterol and triglycerides, although two had borderline high triglycerides. The authors noted a family history of both kidney and lipid metabolism alterations, but other than the previously mentioned lipid levels in the six non-carriers, affected member phenotypes and genotypes were not specified.

The proband transiently improved in response to plasma lipid-lowering treatments, but the treatments had to be altered and she died of intracranial hemorrhage due to hypertension at age 58. After death, her liver appears to have been transplanted into a 65-year-old patient with advanced hepatocarcinoma (Cautero et al., 2010). The identity of the donor is uncertain but based on the proband’s and donor’s shared APOE genotype (APOE2 homozygote carrying the R168C mutation), their age, cause of death, and location, it is likely they were the same person. The organ recipient developed severe lipid abnormalities after the transplant, including elevations of cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in blood. He did not develop renal impairment.

The mutation was also found in a 21-year-old Chinese LPG patient and her mother (Ku et al., 2019). These carriers had no known history of renal disease or lipidosis and only the daughter presented with disease phenotypes, including LPG, splenomegaly, and elevated levels of triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, and ApoE in plasma. APOE exon 4 was sequenced in four individuals, the proband, her mother, and two healthy controls, and the mutation was found only in the former two. The mutation was named after the city of Shenzhen.

The 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 lost in the R168C 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).

Moreover, immunoblotting experiments suggest R168C may induce the formation of ApoE dimers via intermolecular disulphide bridges (Russi et al., 2009; Magistroni et al., 2013). The authors speculated these dimers may destabilize ApoE-containing lipoproteins, facilitating their entrapment in the kidney glomerular capillaries.

There are three additional mutations at this site, two which have been tied to LPG. Also of note, 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. 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.
2. Russi G, Furci L, Leonelli M, Magistroni R, Romano N, Rivasi P, Albertazzi A. Lipoprotein glomerulopathy treated with LDL-apheresis (Heparin-induced Extracorporeal Lipoprotein Precipitation system): a case report. J Med Case Rep. 2009 Dec 2;3:9311. PubMed.
3. Magistroni R, Bertolotti M, Furci L, Fano RA, Leonelli M, Pisciotta L, Pellegrini E, Calabresi L, Bertolini S, Calandra S. Lipoprotein glomerulopathy associated with a mutation in apolipoprotein e. Clin Med Insights Case Rep. 2013;6:189-96. Epub 2013 Dec 5 PubMed.
4. Ku M, Tao C, Zhou AA, Cheng Y, Wan QJ. A novel apolipoprotein E mutation (p.Arg150Cys) in a Chinese patient with lipoprotein glomerulopathy. Chin Med J (Engl). 2019 Jan 20;132(2):237-239. PubMed.
5. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
6. 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.
7. 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.
8. 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.

Other Citations

1. Cautero et al., 2010

Further Reading

No Available Further Reading