Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908773_44908787 GCGCAAGCTGCGTAA>-
Position: (GRCh37/hg19):Chr19:45412030_45412044 GCGCAAGCTGCGTAA>-
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: AAG to -, CTG to -, CGT to -, AAG to -, CGG to -
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant was identified in a Chinese family with five carriers, four suffering from kidney disease (Xie et al., 2019). The proband and his mother, both mutation carriers, had pathologically confirmed cases of lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries dilate and accumulate layered, lipoprotein-rich aggregates. They had elevated protein levels in urine, a symptom of LPG, as well as elevated levels of ApoE and ApoB in blood.

In addition, one of the proband’s younger brothers carried the mutation and had elevated protein in the urine, and elevated levels of lipids and ApoB in blood, but pathological data were unavailable to confirm LPG. Another brother also carried the mutation and had elevated protein in urine, but was diagnosed with IgA nephropathy by renal biopsy. The authors noted this patient may also have LPG lesions that went undetected. Interestingly, the proband’s daughter, who was also a carrier, was asymptomatic with normal kidney function and normal blood lipid levels, although levels of ApoE, ApoA, and ApoB were not assessed. The authors noted this case may indicate incomplete penetrance.

The proband’s father and the proband’s younger brother did not carry the variant and had no symptoms of kidney disease although, of note, the father had elevated levels of lipids and ApoE in blood.

Biological Effect

The biological effect of this mutation is unknown, but several studies indicate that the missing amino acids are importantly involved in ApoE’s binding to cell surface receptors, including the low-density lipoprotein receptor (LDLR) (Zaiou et al., 2000; Lund-Katz et al., 2011), LDLR-related protein 1 (Guttman et al., 2010), and heparan sulfate proteoglycans (Libeu et al., 2011; Futamura et al., 2005; Mah et al., 2023). Interestingly, individually substituting adenines at four of the five deleted positions (K161, L162, K164, R165) 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).

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References

Paper Citations

1. Xie W, Xie Y, Lin Z, Xu X, Zhang Y. A novel apolipoprotein E mutation caused by a five amino acid deletion in a Chinese family with lipoprotein glomerulopathy: a case report. Diagn Pathol. 2019 May 15;14(1):41. PubMed.
2. Zaiou M, Arnold KS, Newhouse YM, Innerarity TL, Weisgraber KH, Segall ML, Phillips MC, Lund-Katz S. Apolipoprotein E;-low density lipoprotein receptor interaction. Influences of basic residue and amphipathic alpha-helix organization in the ligand. J Lipid Res. 2000 Jul;41(7):1087-95. PubMed.
3. Lund-Katz S, Wehrli S, Zaiou M, Newhouse Y, Weisgraber KH, Phillips MC. Effects of polymorphism on the microenvironment of the LDL receptor-binding region of human apoE. J Lipid Res. 2001 Jun;42(6):894-901. PubMed.
4. Guttman M, Prieto JH, Handel TM, Domaille PJ, Komives EA. Structure of the minimal interface between ApoE and LRP. J Mol Biol. 2010 Apr 30;398(2):306-19. Epub 2010 Mar 19 PubMed.
5. Libeu CP, Lund-Katz S, Phillips MC, Wehrli S, Hernáiz MJ, Capila I, Linhardt RJ, Raffaï RL, Newhouse YM, Zhou F, Weisgraber KH. New insights into the heparan sulfate proteoglycan-binding activity of apolipoprotein E. J Biol Chem. 2001 Oct 19;276(42):39138-44. Epub 2001 Aug 10 PubMed.
6. Futamura M, Dhanasekaran P, Handa T, Phillips MC, Lund-Katz S, Saito H. Two-step mechanism of binding of apolipoprotein E to heparin: implications for the kinetics of apolipoprotein E-heparan sulfate proteoglycan complex formation on cell surfaces. J Biol Chem. 2005 Feb 18;280(7):5414-22. Epub 2004 Dec 6 PubMed.
7. Mah D, Zhu Y, Su G, Zhao J, Canning A, Gibson J, Song X, Stancanelli E, Xu Y, Zhang F, Linhardt RJ, Liu J, Wang L, Wang C. Apolipoprotein E Recognizes Alzheimer's Disease Associated 3-O Sulfation of Heparan Sulfate. Angew Chem Int Ed Engl. 2023 Jun 5;62(23):e202212636. Epub 2023 Apr 28 PubMed.
8. 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.

Further Reading

No Available Further Reading