Overview

Clinical Phenotype: Cardiovascular Disease, Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44907865 G>A
Position: (GRCh37/hg19):Chr19:45411122 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs762461580
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to CAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This variant was identified in a 28-year-old Chinese man with a rare kidney disorder, lipoprotein glomerulopathy (LPG), who also carried APOE R43C, a known risk factor for LPG (Li et al, 2022). LPG is characterized by the accumulation of layered, lipoprotein-rich aggregates in the glomerular capillaries of the kidney. Interestingly, the man’s father carried R43C, while his mother carried R50H, and neither of them had kidney disease.

The authors noted that R50H has also been found in patients with familial hypercholesterolemia and early onset coronary heart disease, but no references were provided.

Four heterozygotes were reported in the gnomAD variant database, three of whom were of East Asian ancestry (gnomAD v2.1.1, March 2022).

Biological Effect

The biological effect of this variant is unknown, but CADD, a tool that integrates diverse information in silico, predicted R50H is deleterious (PHRED-scaled CADD = 23). Also of note, an artificial substitution at this same site, R50A, 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, a study using FRET and computational simulations to study monomeric ApoE4 predicted interactions between R50, in helix 1 of ApoE's N-terminal domain, and E88, in helix 2. These contacts were predicted to occur when the C-terminal domain is undocked from the N-terminal helix bundle, a form suspected to enable lipid binding (Stuchell-Brereton et al., 2023).

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References

Mutations Citations

1. APOE R43C (Kyoto)

Paper Citations

1. Li Y, Chen J, Zou Y, Wang W, Li G. Lipoprotein glomerulopathy resulting from compound heterogeneous mutations of APOE gene: A case report. Medicine (Baltimore). 2022 Feb 4;101(5):e28718. PubMed.
2. 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.
3. 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.

Further Reading

No Available Further Reading