Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Cardiovascular Disease, Kidney Disorder: Lipoprotein Glomerulopathy
Reference Assembly: GRCh37/hg19
Position: Chr19:45412080 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: CGC to CCC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This mutation, affecting the same arginine that is substituted in the common ApoE isoform R176C (APOE2), has been reported in at least nine individuals, most suffering from lipoprotein glomerulopathy (LPG). This rare disorder is characterized by enlargement of the glomerular capillaries of the kidney with accumulation of layered, lipoprotein-rich aggregates (Saito et al., 2020, Li et al., 2022).

The variant was first reported in two unrelated Japanese patients with LPG (Tokura et al., 2011, Mitani et al., 2011). Both patients, men aged 26 and 45, presented with protein in their urine, a sign of kidney malfunction, and were subsequently diagnosed with LPG after pathological examination of kidney biopsies. They both also had mild dyslipidemia. Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were moderately elevated in the 45-year-old (Mitani et al., 2011), while only triglycerides were elevated in the 26-year-old (Tokura et al., 2011). In both cases, the levels of lipoprotein (a), an LDL form associated with atherosclerosis and cardiovascular disease, were normal. Unlike other LPG patients in which ApoE levels are elevated in serum, both carriers had normal ApoE levels. However, as in other cases of LPG, ApoE was found in the 26-year-old’s glomerular capillary walls.

Assessment of the patients’ ApoE isoforms by isoelectric focusing and restriction enzyme digestion suggested an APOE2/3 genotype, but DNA sequencing revealed that the ApoE2-like species were in fact due to an R176P substitution. The patients were not known to be related but might have had a common ancestor (Saito and Matsunaga 2011). ApoE Osaka/Kurashiki was proposed as the name of this mutation, referencing the two cities in which the mutation was discovered.

The mutation was subsequently found in five Chinese individuals. In a study from Shanghai, a family spanning two generations with three mutation carriers was identified (Yang et al., 2020a). Two carriers suffered from LPG and one was asymptomatic. In the same study, a carrier from a different family was identified, but neither the mutation nor the disease was observed in members of his family, including his parents. Both probands had high blood pressure, as well as elevated levels of triglycerides and total cholesterol. Unlike the original Japanese patients, these individuals also had elevated ApoE. Their APOE genotypes were reported as APOE3/3 and APOE3/4 (presumbaly based solely on the variants encoding amino acid 130, since the 176 amino acid was determined by the mutation). The mutation was also found in a Tibetan Chinese LPG patient (Yang et al., 2020b).

The variant was more recently identified in two unrelated Brazilian patients, both diagnosed with LPG (da Silveira-Neto et al., 2021). Both carriers were Caucasian men who reported having no known Asian ancestry. Only one of them had a family history of kidney disease.

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

Biological effect

Although the biological effects of this mutation are unknown, biochemical analyses suggest it leads 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 R176 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 formed discoidal particles that appeared normal under the electron microscope, several clusters of poorly formed particles were also observed. The authors hypothesized the mutation induces a generalized unfolding of the N-terminal domain.

Other structural predictions also point to R176 being key to ApoE conformation. R176 is part of a region in helix 4, between residues 173 and 180, that is highly conserved in evolution and thought to be involved in the propagation of structural changes in the C-terminal domain (Frieden et al., 2015). An NMR study of an APOE3-like construct predicted R176 is involved in the separation of ApoE’s N-terminal helices 3 and 4, and the subsequent dimerization of ApoE3 monomers (Chen et al., 2011). A study using FRET and computational simulations to analyze monomeric ApoE4, predicted an interaction between R176, in helix 4, and E114, in helix 3 (Stuchell-Brereton et al., 2023).

In silico algorithms, including SIFT, PolyPhen2 and PANTHER, predicted that R176P is damaging (Yang et al., 2020b). Consistently, its 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 R176C (ApoE2)

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. Li MS, Li Y, Liu Y, Zhou XJ, Zhang H. An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne). 2022;9:905007. Epub 2022 May 6 PubMed.
3. Tokura T, Itano S, Kobayashi S, Kuwabara A, Fujimoto S, Horike H, Satoh M, Komai N, Tomita N, Matsunaga A, Saito T, Sasaki T, Kashihara N. A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. J Atheroscler Thromb. 2011;18(6):536-41. Epub 2011 Apr 4 PubMed.
4. Mitani A, Ishigami M, Watase K, Minakata T, Yamamura T. A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy. J Atheroscler Thromb. 2011;18(6):531-5. Epub 2011 Feb 16 PubMed.
5. Saito T, Matsunaga A. Significance of a novel apolipoprotein E variant, ApoE Osaka/Kurashiki, in lipoprotein glomerulopathy. J Atheroscler Thromb. 2011;18(6):542-3. Epub 2011 Jun 13 PubMed.
6. 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.
7. Yang Z, Wu H, Hu Z. [Discovery of a Chinese Tibetan patient with lipoprotein glomerulopathy due to APOE Osaka/Kurashiki variant]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2020 Feb 10;37(2):166-169. PubMed.
8. da Silveira-Neto JN, de Oliveira Ahn GJ, de Menezes Neves PD, Baptista VA, de Almeida Araújo S, Wanderley DC, Watanabe A, Watanabe EH, Murai NM, Bertollo EM, Vieira-Neto OM, Dantas M, de Antônio SR, Costa RS, Baptista MA, Moysés-Neto M, Onuchic LF. Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America. Diagn Pathol. 2021 Jul 26;16(1):65. PubMed.
9. 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.
10. 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.
11. Frieden C. ApoE: the role of conserved residues in defining function. Protein Sci. 2015 Jan;24(1):138-44. Epub 2014 Dec 9 PubMed.
12. Chen J, Li Q, Wang J. Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14813-8. Epub 2011 Aug 22 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