Overview

Clinical Phenotype: Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908803_44908804 ->GAT
Position: (GRCh37/hg19):Chr19:45412060_45412061 ->GAT
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Duplication
Expected RNA Consequence: Duplication
Expected Protein Consequence: Duplication
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was found in a Japanese 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 (Yokochi et al., 2024; Matsunaga and Saito, 2014). At 23 years of age, he had elevated protein levels in urine (proteinuria), and at 33 years he was admitted to a hospital with severe proteinuria. Renal biopsy showed lesions consistent with LPG. Unlike most LPG patients, he had normal ApoE levels in blood. He also had no signs of hyperlipidemia. The carrier died at age 46 from end-stage kidney disease. Of note, the carrier’s father had an undiagnosed kidney disorder.

Upon isoelectric focusing, the patient’s ApoE isoforms migrated to the positions of the common ApoE alleles, ApoE2 (R176C) and ApoE3. DNA sequencing of APOE exons 3 and 4 revealed a single mutation, the D169 duplication, suggesting this alteration was responsible for the ApoE2-like isoelectric migration.

This variant was absent from the gnomAD variant database (v2.1.1, May 2022).

Biological effect

The biological effect of this variant is unknown. D169 borders ApoE’s receptor binding site and is highly conserved (Frieden et al. 2015). Moreover, it has been identified as a potential cleavage site that could generate a toxic N-terminal fragment when derived from isoform C130R (ApoE4). One study reported this fragment localizes to microglial cell nuclei (Love et al., 2017). In addition, a study using FRET and computational simulations to study monomeric ApoE4 predicted long-range interactions between D169, on N-terminal helix 4, and R121, on helix 3, possibly stabilizing the N-terminal helix bundle (Stuchell-Brereton et al., 2023).

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References

Mutations Citations

1. APOE R176C (ApoE2)
2. APOE C130R (ApoE4)

Paper Citations

1. Yokochi A, Matsunaga A, Kanemoto K, Tominaga N, Uda S, Saito T. Lipoprotein glomerulopathy with a novel apolipoprotein E variant, APOE Kanto (Asp 151dup). CEN Case Rep. 2024 Aug 14; PubMed.
2. Matsunaga A, Saito T. Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia. Clin Exp Nephrol. 2014 Apr;18(2):220-4. Epub 2014 Feb 26 PubMed.
3. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
4. Love JE, Day RJ, Gause JW, Brown RJ, Pu X, Theis DI, Caraway CA, Poon WW, Rahman AA, Morrison BE, Rohn TT. Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the Alzheimer's disease brain. Int J Physiol Pathophysiol Pharmacol. 2017;9(2):40-57. Epub 2017 Apr 15 PubMed.
5. 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