Overview

Clinical Phenotype: Kidney Disorder: Lipoprotein Glomerulopathy, Blood Lipids/Lipoproteins
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 was identified in a 36-year-old man diagnosed with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Bomback et al., 2010; Saito et al., 2020). His lipid profile in blood included elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, and normal levels of low-density lipoprotein (LDL) cholesterol. Unlike most LPG patients who are of East Asian ancestry, this individual was European-American. 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.

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. 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