Overview

Clinical Phenotype: Kidney Disorder: Lipoprotein Glomerulopathy
Reference Assembly: GRCh37/hg19
Position: Chr19:45412058_45412060 ->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 an individual diagnosed with lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (unpublished, listed in Matsunaga and Saito, 2014; Saito et al., 2020). Upon isoelectric focusing, the patient’s ApoE isoforms migrated to the positions of the common ApoE alleles, ApoE2 (R176C) and ApoE3. However, it is uncertain which of these two migration patterns was affected by the extra negative charge contributed by the D169dup variant, so the APOE alleles of the carrier remain unknown.

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. 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.
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. 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