Overview

Clinical Phenotype: Blood Lipids/Lipoproteins, Kidney Disorder: Lipoprotein Glomerulopathy
Position: (GRCh38/hg38):Chr19:44908780_44908788 CTGCGTAAG>-
Position: (GRCh37/hg19):Chr19:45412037_45412045 CTGCGTAAG>-
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: CTG to -, CGT to -, AAG to -
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This mutation results in the loss of three amino acids in the ApoE receptor-binding region. It is a risk factor for 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). More than 15 LPG patients carrying this mutation have been reported, making it one of the variants most frequently associated with the disease. Also of note, affected carriers develop LPG, on average, at a younger age (20 years) than those carrying other LPG mutations (Li et al., 2022).

The mutation was first reported by two independent groups in Japan (Konishi et al., 1999, Ogawa et al., 2000). In 1997, Ogawa and co-workers described an 8-year-old Japanese girl with LPG who experienced kidney malfunction starting at age 4 (Maruyama et al., 1997). In addition to kidney pathology, she had hyperlipidemia and elevated ApoE levels in plasma. Although her genotype was homozygous for the common APOE isoform APOE3, analysis of her ApoE protein by isoelectric focusing revealed a more negatively charged band in addition to the expected ApoE3 band. The girl’s mother and brother also had the anomalous band and high plasma ApoE levels, but no renal abnormalities. The authors suspected a genetic alteration, and in a subsequent study identified the mutation and named it Maebashi, after their city of residence. As expected from the migration pattern of their ApoE proteins, the mother and brother were also carriers, indicating incomplete penetrance (Ogawa et al., 2000).

A few months prior to this publication, researchers in Tokyo reported a 56-year-old Japanese man with LPG and elevated ApoE levels and intermediate-density lipoprotein (IDL) cholesterol in plasma (Konishi et al., 1999). Like the little girl’s ApoE, this man’s ApoE migrated to an altered position upon isoelectric focusing, indicating the presence of a more negatively charged species. Sequencing revealed a three-amino acid deletion which they named Tokyo. 

Whereas Konishi and co-workers described the deletion as including either L159 to K161 or K161 to R163, Ogawa ‘s group described it as spanning R160 to L162. In fact, all three deletions result in the same nucleotide and amino acid sequences. Following the HGVS nomenclature guidelines (v. 20.05), we refer to it as L162_K164del, where L162 corresponds to the first amino acid missing in the mutant protein sequence. Also, in line with the HGVS guidelines, we assign the nucleotide deletion to the most C-terminal position (3’ rule).

Since these original reports, several other heterozygous carriers, all of Asian ancestry, have been described (Chen et al., 2003, Han et al., 2010, Hamatani et al., 2010, Han et al., 2012, Takasaki et al., 2015, Ting et al., 2022).  In one study, the presence of the mutation in four of six unrelated Chinese LPG patients and its absence in 200 controls suggested the mutation might be a fairly common cause of LPG in China (Han et al., 2010). However, the mutation was not found in another study of 17 Chinese LPG patients (Chen et al., 2007). Differences in prevalence within the country may explain the discrepancy—most cases in China have been identified in Beijing (Li et al., 2022).

Several studies have shown that not all L162_K164del carriers develop LPG, but those with no signs of renal disease have been reported to have elevated lipids and ApoE in blood (e.g., Han et al., 2010). In this study, some of the affected carriers, but none of the unaffected ones, also had elevated levels of ApoB.

Some clues to the relationship between L162_K164del and the common APOE alleles, APOE2,3, and 4, have emerged. Han and colleagues deduced the deletion occurred on an APOE3 background in the two families they studied (Han et al., 2010). They also found, presumably in trans, APOE2 and APOE4 in several mutation carriers. Interestingly, both affected and unaffected L162_K164del carriers were associated with each of the three APOE backgrounds they observed, APOE3/3, APOE2/3, and APOE4/3. At first blush, this suggests the common APOE alleles contribute little to the phenotypes of L162_K164del carriers. However, a subsequent study revealed a unique renal pathology that appears to be due to the joint effects of L162_K164del mutation and APOE2 (Takasaki et al., 2015). In this case, a 25-year-old Japanese carrier presented with both the typical lipoprotein-rich aggregates of LPG, as well as with an infiltration of lipid-laden “foamy” macrophages in his kidney glomeruli. These foamy macrophages have been described in APOE2 homozygotes who develop another type of kidney glomerulopathy, but are rarely seen in LPG patients.

Biological Effect

As in the case of other LPG-associated mutations, L162_K164del is thought to have effects on systemic lipid physiology, as well as localized effects in the kidney. Indeed, although plasma lipid-lowering medications ameliorate LPG in some patients, they are not always effective (Han et al., 2010). ApoE expression by macrophages may contribute to the mutation’s localized effects (Saito et al., 2020).

The effects of this mutation at the cellular and molecular levels are unknown, but based on its location, it is expected to alter receptor binding (e.g., Guttman et al., 2010). Interestingly, individually substituting adenines at positions L162 and K164 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). Also of note, L162 and R163 are within ApoE’s main heparin-binding site and may be important for ApoE's interaction with the sulfo groups of heparan sulfate proteoglycans (Libeu et al., 2001), particularly L162 (Mah et al., 2023).

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References

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. Konishi K, Saruta T, Kuramochi S, Oikawa S, Saito T, Han H, Matsunaga A, Sasaki J. Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83(3):214-8. PubMed.
4. Ogawa T, Maruyama K, Hattori H, Arai H, Kondoh I, Egashira T, Watanabe T, Kobayashi Y, Morikawa A. A new variant of apolipoprotein E (apo E Maebashi) in lipoprotein glomerulopathy. Pediatr Nephrol. 2000 Feb;14(2):149-51. PubMed.
5. Maruyama K, Arai H, Ogawa T, Tomizawa S, Morikawa A. Lipoprotein glomerulopathy: a pediatric case report. Pediatr Nephrol. 1997 Apr;11(2):213-4. PubMed.
6. Chen YQ, Zhang H, Zhu SL, Zou WZ, Wang M, Liu ZS, Wang HY. [A 3-amino acid deletion of apolipoprotein E found in 3 Chinese lipoprotein glomerulopathy patients]. Zhonghua Yi Xue Za Zhi. 2003 May 10;83(9):774-7. PubMed.
7. 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.
8. Hamatani H, Hiromura K, Kobatake K, Yoshida H, Kobayashi S, Yoneda N, Kayakabe K, Matsumoto T, Kuroiwa T, Ueki K, Nojima Y. Successful treatment of lipoprotein glomerulopathy in a daughter and a mother using niceritrol. Clin Exp Nephrol. 2010 Dec;14(6):619-24. Epub 2010 Sep 15 PubMed.
9. Han HL, Lin S, Sun LS, Zhang P, Zhai DP. [Identification of a mutation in exon 4 of apolipoprotein E gene in a family affected with lipoprotein glomerulopathy]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2012 Apr;29(2):141-4. PubMed.
10. Takasaki S, Maeda K, Joh K, Yamakage S, Fukase S, Takahashi T, Suzuki M, Matsunaga A, Saito T. Macrophage Infiltration into the Glomeruli in Lipoprotein Glomerulopathy. Case Rep Nephrol Dial. 2015 Sep-Dec;5(3):204-12. Epub 2015 Dec 15 PubMed.
11. Ting JA, McRae SA, Schwartz D, Barbour SJ, Riazy M. Lipoprotein Glomerulopathy, First Case Report from Canada. Int J Nephrol Renovasc Dis. 2022;15:207-214. Epub 2022 Jun 21 PubMed.
12. Chen S, Liu ZH, Zheng JM, Zhang X, Li LS. A complete genomic analysis of the apolipoprotein E gene in Chinese patients with lipoprotein glomerulopathy. J Nephrol. 2007 Sep-Oct;20(5):568-75. PubMed.
13. 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.
14. 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.
15. 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.
16. 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.

Further Reading