Overview

Clinical Phenotype: Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908790 G>C
Position: (GRCh37/hg19):Chr19:45412047 G>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CCG
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This mutation has been identified in several individuals, most suffering from lipoprotein glomerulopathy (LPG), a rare kidney disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Saito et al., 2020).

R165P was first reported in a Mexican man with LPG living in Chicago (Sam et al., 2006). He was homozygous for the mutation on an APOE3/3 background. Based on this original report, the mutation is sometimes referred to as ApoE Chicago. The mutation was subsequently reported in two Chinese LPG patients: a middle-aged man who also had an APOE3/3 genotype (Yang et al., 2020), and a man in his 20s who initially presented with hyperlipidemia—including elevated triglycerides and ApoE levels in blood—and nephrotic syndrome, a kidney disorder characterized by protein in the urine (Liu et al., 2024). Of note, the mother of the latter patient also carried R165P, but had no signs of kidney dysfunction, such as protein or blood in the urine, and her ApoE levels were normal.

R165P has also been found together with another LPG-relevant mutation, E21K. A 51-year-old Japanese woman and her mother were identified as carriers of the two mutations on the same chromosome (Kodera et al., 2017). The daughter suffered from LPG, but the mother appeared to be healthy. Unlike her daughter, the mother carried the C130R (APOE4) variant in trans.

Also, in the same study, the authors identified another Japanese LPG patient carrying both R165P and E21K mutations. Although the families were not known to be related, the mothers of both probands came from the same city. An earlier report of this patient had been described as carrying the APOE2 allele and E21K, but the R165P mutation had not been identified (Miyata et al., 1999). Interestingly, this patient received a kidney transplant which appeared healthy at the time of transplantation, but developed LPG pathology within nine months, suggesting blood-derived ApoE plays an important role in this disorder.

R165P is absent from the gnomAD variant database (gnomAD v2.1.1, May 2021).

Biological Effect

Although the biological effects of this mutation are unknown, several studies suggest it may result in both loss-of-function and gain-of-function alterations. One study reported in vitro binding of mutant, but not control, ApoE to glomerular capillaries in kidney sections from a healthy control (Sam et al., 2006). Moreover, the mutation’s position suggests it likely affects ApoE’s binding to cell surface proteins. R165P resides in the ApoE receptor binding region, a sequence highly conserved across species (Frieden et al., 2015). Interestingly, an artificial substitution at this site with another aromatic aliphatic amino acid, R165A, 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). In addition, R165 has been identified as a key residue for ApoE's interaction with the sulfo groups of heparan sulfate proteoglycans (HSPGs) in ApoE’s main heparin-binding site (Libeu et al., 2001, Mah et al., 2023).

Biochemical analyses suggest the mutation may also lead to consequential changes in protein structure. In line with proline’s known ability to introduce kinks in helices and act as a helix breaker in globular proteins, the substitution of R165 with a proline appears to reduce ApoE helical content (Georgiadou et al., 2013). In addition, the mutation was reported to increase exposure of hydrophobic residues to the surrounding solvent, and thermodynamically destabilize ApoE’s structure, likely disrupting its oligomerization properties, and making it prone to aggregation and more susceptible to proteases (Georgiadou et al., 2013; Stratikos and Chroni 2013). Although the mutant protein forms discoidal particles that appeared normal under the electron microscope, a few had altered sizes and shapes. The authors hypothesized the mutation induces a generalized unfolding of the N-terminal domain.

Also of note, a study using FRET and computational simulations to study monomeric ApoE4, predicted R165 contacts D125 when the C-terminal domain is undocked from the N-terminal helix bundle, a configuration suspected to be compatible with lipid binding (Stuchell-Brereton et al., 2023). R165 resides in helix 4 of the N-terminal domain, while D125 is in helix 3.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, May 2022).

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References

Mutations Citations

1. APOE E21K
2. APOE C130R (ApoE4)

Paper Citations

1. 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.
2. Sam R, Wu H, Yue L, Mazzone T, Schwartz MM, Arruda JA, Dunea G, Singh AK. Lipoprotein glomerulopathy: a new apolipoprotein E mutation with enhanced glomerular binding. Am J Kidney Dis. 2006 Mar;47(3):539-48. PubMed.
3. Yang M, Weng Q, Pan X, Hussain HM, Yu S, Xu J, Yu X, Liu Y, Jin Y, Zhang C, Li X, Ren H, Chen N, Xie J. Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations. Mol Genet Genomic Med. 2020 Aug;8(8):e1281. Epub 2020 May 22 PubMed.
4. Liu Y, Cheng Y, Wen Y, Li C, Chen G, Li M. A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation. BMC Nephrol. 2024 Mar 6;25(1):87. PubMed.
5. Kodera H, Mizutani Y, Sugiyama S, Miyata T, Ehara T, Matsunaga A, Saito T. A Case of Lipoprotein Glomerulopathy with apoE Chicago and apoE (Glu3Lys) Treated with Fenofibrate. Case Rep Nephrol Dial. 2017 May-Aug;7(2):112-120. Epub 2017 Jul 27 PubMed.
6. Miyata T, Sugiyama S, Nangaku M, Suzuki D, Uragami K, Inagi R, Sakai H, Kurokawa K. Apolipoprotein E2/E5 variants in lipoprotein glomerulopathy recurred in transplanted kidney. J Am Soc Nephrol. 1999 Jul;10(7):1590-5. PubMed.
7. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 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.
9. 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.
10. 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.
11. Georgiadou D, Stamatakis K, Efthimiadou EK, Kordas G, Gantz D, Chroni A, Stratikos E. Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy. J Lipid Res. 2013 Jan;54(1):164-76. Epub 2012 Oct 30 PubMed.
12. Stratikos E, Chroni A. A possible structural basis behind the pathogenic role of apolipoprotein E hereditary mutations associated with lipoprotein glomerulopathy. Clin Exp Nephrol. 2014 Apr;18(2):225-9. Epub 2013 Oct 23 PubMed.
13. 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