Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908805 C>A
Position: (GRCh37/hg19):Chr19:45412062 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to GAC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been identified in two patients with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates. Unlike most LPG patients who are of East Asian ancestry, these individuals were of European ancestry.

The first carrier was a 36-year-old American man whose lipid profile in blood included elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, and normal levels of low-density lipoprotein (LDL) cholesterol (Bomback et al., 2010; Saito et al., 2020). The mutation was named ApoE Las Vegas after the city in which he lived. Four of the carrier’s relatives were genotyped, revealing that the patient’s mother and one of his two children carried the mutation. However, none of the relatives had signs of kidney disease or abnormal lipid profiles in blood.

The second carrier was a 63-year-old Dutch man diagnosed with LPG who had a lipid blood profile consistent with hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia (Mulder et al., 2024). He had an APOE3/APOE4 genotype.

This variant was absent from the gnomAD variant database (v2.1.1, Nov 2021).

Biological Effect

This variant has been shown to be aggregation-prone as assessed by dynamic light-scattering and by measurements of its binding to the amyloid probe thioflavin T (Katsarou et al., 2018). It was reported to reduce helical content and cause thermodynamic destabilization predicted to induce protein misfolding. Also of note, A170 borders the ApoE receptor-binding site, a region harboring multiple variants tied to LPG.

However, this variant’s PHRED-scaled CADD score, which integrates diverse information in silico, was 14.74, below the commonly used deleteriousness threshold of 20 (CADD v.1.6, May 2022).

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References

Paper Citations

1. Bomback AS, Song H, D'Agati VD, Cohen SD, Neal A, Appel GB, Rovin BH. A new apolipoprotein E mutation, apoE Las Vegas, in a European-American with lipoprotein glomerulopathy. Nephrol Dial Transplant. 2010 Oct;25(10):3442-6. Epub 2010 Jul 11 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. Mulder JW, 't Hart N, Mulder MT, Zuurbier L, Roeters van Lennep JE. A case of lipoprotein glomerulopathy due to the pathogenic APOE Las Vegas variant c.509C>A: p. (Ala170Asp). J Clin Lipidol. 2024 Dec 4; Epub 2024 Dec 4 PubMed.
4. Katsarou M, Stratikos E, Chroni A. Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy. J Lipid Res. 2018 Dec;59(12):2339-2348. Epub 2018 Oct 11 PubMed.

Further Reading

No Available Further Reading