Overview

Clinical Phenotype: Kidney Disorder, Hyperlipoproteinemia Type III
Position: (GRCh38/hg38):Chr19:44908940 C>G
Position: (GRCh37/hg19):Chr19:45412197 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: TCC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been identified in four Japanese individuals with a unique kidney pathology similar to a condition known as membranous nephropathy (Saito et al., 2020; Koshino et al., 2022). They were all homozygous for the common R176C (APOE2) allele, and also carried S215C. Kidney pathology has been previously observed in a few APOE2 homozygotes (known as ApoE2 homozygote glomerulopathy), however, the presence of S215C appears to modify the phenotype.

S215C was initially found in a 20-year-old woman with protein and blood in her urine (Fukunaga et al., 2018). A biopsy revealed thickened small blood vessels in kidney glomeruli with large, layered subepithelial deposits and projections of the basement membrane known as spikes, similar to those found in membranous nephropathy. Although the deposits looked like ones formed as a secondary effect of autoimmune disorders, immune factors such as immunoglobulins and complement were absent, and instead ApoE was present at high levels. ApoE was also elevated in serum twofold, although hyperlipidemia was not detected. Genotyping revealed APOE2 homozygosity and the S215C variant.

Two other carriers also had kidney disease and high levels of ApoE in serum, but unlike the original carrier, they also had high levels of triglycerides in blood (Hirashima et al., 2018 and Kato et al., 2019). Both were men, 47- and 79-years-old, and had hyperlipoproteinemia type III (HLPP3), a condition resulting in abnormal lipid profiles in blood and most often caused by APOE2 homozygosity. Moreover, although their kidney biopsies revealed large lipoprotein deposits and basement membrane spikes, they were different in appearance and showed signs of damage related to APOE2 homozygosity, including lipid-laden macrophages known as foam cells.

Electron microscopic analysis of a kidney biopsy of yet another case, a 28-year-old man with moderate levels of protein and blood in urine, revealed massive deposits resembling microbubbles that were larger than those observed in previous cases (Koshino et al., 2022). In addition to their subepithelial location, they were found in subendothelial and paramesangial areas, and appeared to have caused partial degeneration of the glomerular basement membrane. This severe pathology contrasted with the patient’s mild clinical profile. Neither foam cells nor lipoprotein thrombi were observed. Serum triglyceride and cholesterol levels were normal, but ApoE levels were elevated.

Thus, the phenotype associated with this variant, on the same APOE2/E2 background, varies between individuals (Saito et al., 2020). Some of the variations may be due to differences in disease stage (Koshino et al., 2022).

This variant was absent from the gnomAD variant database (v2.1.1, May 2022). Of note, all carriers reported to date are from the west-central region of mainland Japan.

Biological Effect

The biological effect of this variant is unknown. As noted by Saito and colleagues, S215C lies within the hinge region of ApoE which may affect interactions between the N- and C-terminal domains, affecting receptor and/or lipid binding (Saito et al., 2020).

Of note, S215C is glycosylated in both plasma (10 percent) and cerebrospinal fluid (27 percent) (Flowers et al., 2020). The glycosylation was predicted to have little or no effect on the conformational changes required for receptor binding.

This variant’s PHRED-scaled CADD score (19.54), which integrates diverse information in silico, was just below the commonly used threshold of 20 to predict deleteriousness (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. Koshino A, Takaeda C, Matsuno T, Kitajima S, Iwata Y, Sakai N, Nagahama K, Niida Y, Saito T, Yokoyama H, Wada T. Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits. Case Rep Nephrol Dial. 2022 May-Aug;12(2):96-104. Epub 2022 Jun 10 PubMed.
3. Fukunaga M, Nagahama K, Aoki M, Shimizu A, Hara S, Matsunaga A, Muso E, Saito T. Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2. Case Rep Nephrol Dial. 2018 Jan-Apr;8(1):45-55. Epub 2018 Mar 20 PubMed.
4. Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E, Saito T. A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep. 2019 May;8(2):106-111. Epub 2019 Jan 30 PubMed.
5. Flowers SA, Grant OC, Woods RJ, Rebeck GW. O-glycosylation on cerebrospinal fluid and plasma apolipoprotein E differs in the lipid-binding domain. Glycobiology. 2020 Jan 28;30(2):74-85. PubMed.

Other Citations

1. Hirashima et al., 2018

Further Reading

No Available Further Reading