Overview

Clinical Phenotype: Multiple Conditions
Position: (GRCh38/hg38):Chr19:44907843 C>T
Position: (GRCh37/hg19):Chr19:45411100 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918399
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 3

Findings

This mutation is one of the two main genetic risk factors for lipoprotein glomerulopathy (LPG), a rare disorder in which the glomerular capillaries of the kidney dilate and accumulate layered, lipoprotein-rich aggregates (Saito et al., 2020).

The inheritance of R43C in LPG has been described as dominant with incomplete penetrance (Han et al., 2010; Hu et al., 2014; Koopal et al., 2017). Although most reports describe LPG developing in adult patients, with an average age at onset of 38 years, pediatric cases have been reported (Liao et al., 2012; Song et al., 2021; Li et al., 2022). Moreover, patients with R43C appear to develop more severe renal dysfunction compared with carriers of other LPG mutations (Li et al., 2022). In one case, severe hypertension with thrombotic microangiopathy (the formation of microscopic blood clots in capillaries and small arteries) was also observed (Wu et al., 2013).

R43C was first identified in a 32-year-old Japanese man with LPG that progressed to chronic renal failure (Matsunaga et al., 1999; Komatsu et al., 1995). Before treatment, the patient had highly elevated levels of plasma cholesterol, triglycerides, and ApoE. Moreover, the electrophoretic migration of his lipoprotein particles indicated accumulation of chylomicron and very-low-density lipoprotein (VLDL) remnants typical of hyperlipoproteinemia type III, a disease associated with several other APOE mutations (Koopal et al., 2017). He also carried one copy of the C130R (APOE4) variant. The patient’s mother was also an R43C carrier but was homozygous for the APOE3 allele. Although she showed no signs of renal or cardiovascular disease, her plasma levels of cholesterol associated with VLDL and with intermediate-density lipoprotein (IDL), as well as her total triglycerides, were elevated. The R43C variant was absent from 120 healthy Japanese controls.

Since this initial study, the mutation has been identified in more than 50 patients, mostly of East Asian ancestry (Li et al., 2022). In China, it is the most common mutation associated with LPG (Song et al., 2021; Han et al., 2010; Wu et al., 2013; Li et al., 2014; Hu et al., 2014; Lui et al., 2019; Liu et al., 2022). Mutation carriers have also been reported in Hong Kong (Cheung et al., 2009) and Taiwan (Liao et al., 2012). Caucasian carriers include two unrelated American men of European ancestry (Rovin et al., 2007) and a Greek Caucasian male (Marinaki et al., 2022). One report described R43C as the most frequent mutation associated with LPG in the world, including not only China, but Japan, France, and the U.S. (Li et al., 2022).

Interestingly, the mutation was found at a particularly high frequency in a small, fairly isolated county in the Sichuan Basin of China. In a study of 35 LPG patients, from 31 unrelated Han Chinese families living in this region, the mutation was present in all patients, as well as in 28 asymptomatic family members (Hu et al., 2014). Pedigree analysis revealed the mutation was always found on an APOE3 backbone in this population. The allele frequencies of the common APOE variants, R176C (APOE2), APOE3, and C130R (APOE4), were similar between symptomatic and asymptomatic carriers: 5 to 6 percent, 86 to 88 percent, and 7 to 9 percent, respectively. As expected, all LPG patients had elevated levels of protein in urine, as well as elevated triglycerides and ApoE levels in serum. The serum ApoE and triglyceride levels of asymptomatic carriers were in between those of the patients and noncarriers. This is consistent with findings from a mutation carrier in the U.S. who was asymptomatic but had LPG-like aggregates in approximately 1 percent of her kidney glomeruli (Rovin et al. 2007).

Although the link between kidney dysfunction and blood lipids is not entirely understood, several studies have reported that protein levels in carriers’ urine parallel those of triglycerides and cholesterol in blood, and medications that normalize blood lipid profiles ameliorate LPG (e.g., Usui et al., 2016; Arai et al., 2003; Liao et al., 2012; Lui et al., 2019).

Two R43C carriers have been found to also carry mutations in COL4A, a gene encoding a component of type IV collagen. One of these individuals was an 11-year-old Chinese girl with LPG and Alport syndrome, a common inherited kidney disorder that affects basement membranes (Yang et al., 2024). In addition to APOE R43C, she carried the pathogenic splice site mutation COL4A4 c.930+1G>A. The second individual was a 21-year-old Chinese man, who suffered from LPG and collagen type III glomerulopathy, a condition in which type III collagen accumulates in kidney glomeruli (Liu et al., 2022). Although the latter glomerulopathy is considered sporadic when it develops in adults, the man carried two heterozygous mutations in the COL4A4 gene, one of which, c.4715C>T, was suspected to be pathogenic.  

Two heterozygous carriers, one of East Asian and one of European (Finnish) ancestry were reported in the gnomAD variant database (v2.1.1, Apr 2022).

Biological effect

Although this mutation is upstream of ApoE’s receptor-binding region, an in vitro competition assay using ApoE loaded with the artificial lipid DMPC revealed that the mutant protein’s ability to compete with labeled LDL for binding to cultured fibroblasts was only 10 percent that of wildtype ApoE3 (Matsunaga et al., 1999). The authors speculated that removal of the R43 side chain, which has been suggested to form a salt bridge between the first two helices of ApoE, could result in a change in tertiary structure that affects receptor-binding activity. Consistent with this proposal, a study using FRET and computational simulations to study monomeric ApoE4 predicted interactions between R43, on helix 1, and E95, on helix 2 (Stuchell-Brereton et al., 2023).

In addition, R43C was reported to have reduced helical content and to be thermodynamically unstable, both in lipid-free and lipid-bound forms, exposing a larger portion of its hydrophobic surface to the solvent compared with wild-type ApoE3 (Katsarou et al., 2018). Also, R43C appears to be aggregation-prone, as assessed by dynamic light-scattering measurements and by its enhanced ability to bind the amyloid probe thioflavin T. Of note, R43 is evolutionarily conserved (Yang et al., 2020).

Surprisingly, one report described increased, rather than decreased, binding of very-low-density lipoprotein (VLDL) particles containing mutant ApoE to the surface of cultured human endothelial and hepatic cells (Murano et al., 2002). In the endothelial cells, the ratio of uptake to binding was decreased, suggesting the mutation could contribute to lipoprotein deposition in glomerular capillaries in vivo.

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

Research models

A mouse model carrying this variant was created by injecting adenovirus carrying the mutant human gene into mice lacking endogenous APOE (Wu et al., 2021). LPG-like aggregates containing ApoE were detected in the glomeruli of these animals’ kidneys.

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References

Mutations Citations

1. APOE C130R (ApoE4)
2. 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. Han J, Pan Y, Chen Y, Li X, Xing G, Shi J, Hou P, Zhang H, Wang H. Common apolipoprotein E gene mutations contribute to lipoprotein glomerulopathy in China. Nephron Clin Pract. 2010;114(4):c260-7. Epub 2010 Jan 20 PubMed.
3. Hu Z, Huang S, Wu Y, Liu Y, Liu X, Su D, Tao Y, Fu P, Zhang X, Peng Z, Zhang S, Yang Y. Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int. 2014 Feb;85(2):416-24. Epub 2013 Sep 11 PubMed.
4. Koopal C, Marais AD, Westerink J, Visseren FL. Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy. J Clin Lipidol. 2017 Jan - Feb;11(1):12-23.e1. Epub 2016 Oct 13 PubMed.
5. Liao MT, Tsai IJ, Cheng HT, Lin WC, Chang YW, Lin YH, Tsau YK. A rare cause of childhood-onset nephrotic syndrome: lipoprotein glomerulopathy. Clin Nephrol. 2012 Sep;78(3):237-40. PubMed.
6. Song Y, Yang C, Liu L, Wang H. Case Report: A Pediatric Case of Lipoprotein Glomerulopathy in China and Literature Review. Front Pediatr. 2021;9:684814. Epub 2021 Aug 27 PubMed.
7. 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.
8. Wu Y, Chen X, Yang Y, Wang B, Liu X, Tao Y, Fu P, Hu Z. A case of lipoprotein glomerulopathy with thrombotic microangiopathy due to malignant hypertension. BMC Nephrol. 2013 Feb 28;14:53. PubMed.
9. Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, Tsuji E, Moriyama K, Koga T, Arakawa K, Oikawa S, Saito T, Kita T, Doi T. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999 Aug;56(2):421-7. PubMed.
10. Komatsu T, Kanatsu K, Ochi H, Kita T, Doi T. Lipoprotein glomerulopathy with a new apolipoprotein E phenotype. Am J Kidney Dis. 1995 Jun;25(6):952-3. PubMed.
11. Li W, Wang Y, Han Z, Luo C, Zhang C, Xiong J. Apolipoprotein e mutation and double filtration plasmapheresis therapy on a new Chinese patient with lipoprotein glomerulopathy. Kidney Blood Press Res. 2014;39(4):330-9. Epub 2014 Sep 19 PubMed.
12. Lui DT, Lee AC, Yap DY, Chan GS, Tan KC. A young Chinese man with nephrotic syndrome due to lipoprotein glomerulopathy. J Clin Lipidol. 2019 Mar - Apr;13(2):251-253. Epub 2018 Dec 19 PubMed.
13. Liu H, Luo C, Li Z, Zhang C, Xiong J. The first case of lipoprotein glomerulopathy complicated with collagen type III glomerulopathy and literature review. J Nephrol. 2022 Nov 12; PubMed.
14. Cheung CY, Chan AO, Chan YH, Lee KC, Chan GP, Lau GT, Shek CC, Chau KF, Li CS. A rare cause of nephrotic syndrome: lipoprotein glomerulopathy. Hong Kong Med J. 2009 Feb;15(1):57-60. PubMed.
15. Rovin BH, Roncone D, McKinley A, Nadasdy T, Korbet SM, Schwartz MM. APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy. N Engl J Med. 2007 Dec 13;357(24):2522-4. PubMed.
16. Marinaki S, Kalaitzakis E, Kolovou K, Gakiopoulou H, Stylianou K, Papasotiriou M, Boletis IN. A case of lipoprotein glomerulopathy in a Greek Caucasian male. Int Urol Nephrol. 2022 Apr;54(4):969-970. Epub 2021 Jun 23 PubMed.
17. Usui R, Takahashi M, Nitta K, Koike M. Five-year follow-up of a case of lipoprotein glomerulopathy with APOE Kyoto mutation. CEN Case Rep. 2016 Nov;5(2):148-153. Epub 2016 Mar 4 PubMed.
18. Arai T, Yamashita S, Yamane M, Manabe N, Matsuzaki T, Kiriyama K, Kanayama Y, Himeno S, Matsuzawa Y. Disappearance of intraglomerular lipoprotein thrombi and marked improvement of nephrotic syndrome by bezafibrate treatment in a patient with lipoprotein glomerulopathy. Atherosclerosis. 2003 Aug;169(2):293-9. PubMed.
19. Yang L, Yang G, Guo H. First patient diagnosed with lipoprotein glomerulopathy and Alport syndrome. Nephrology (Carlton). 2024 Sep 27; PubMed.
20. Katsarou M, Stratikos E, Chroni A. Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy. J Lipid Res. 2018 Dec;59(12):2339-2348. Epub 2018 Oct 11 PubMed.
21. 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.
22. Murano T, Matsumura R, Misawa Y, Ozaki H, Miyashita Y, Yoshida S, Sueioshi M, Sugiyama T, Shirai K. Interaction of endothelial cells and triglyceride-rich lipoproteins with apolipoprotein E (Arg-->Cys) from a patient with lipoprotein glomerulopathy. Metabolism. 2002 Feb;51(2):201-5. PubMed.
23. Wu H, Yang J, Liu YQ, Lei S, Yang M, Yang Z, Yang Y, Hu Z. Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice. J Transl Med. 2021 Mar 4;19(1):97. PubMed.

Other Citations

1. Stuchell-Brereton et al., 2023

Further Reading

No Available Further Reading