Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features

Akira Matsunaga; Takao Saito

doi:10.5551/jat.65393

. 2025 Mar 1;32(3):281–303. doi: 10.5551/jat.65393

Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features

Akira Matsunaga ¹, Takao Saito ^2,³

PMCID: PMC11883201 PMID: 39779225

Abstract

Apolipoprotein E (apoE) is a key apoprotein in lipid transport and is susceptible to genetic mutations. ApoE variants have been studied for four decades and more than a hundred of them have been reported. This paper presents an up-to-date review of the function and structure of apoE in lipid metabolism, the E2, E3, and E4 isoforms, the APOE gene, and various pathologies, such as familial type III hyperlipidemia and lipoprotein glomerulopathy, caused by apoE variants. Alzheimer’s disease was barely mentioned in this paper. But this review should help researchers obtain a comprehensive overview of human apoE in lipid metabolism.

Keywords: Apolipoprotein E, Variant, Mutation, Deficiency, Type III hyperlipidemia, Dysbetalipoproteinemia, Lipoprotein glomerulopathy

Introduction

Apolipoprotein E (apoE) is one of the key apolipoproteins in blood lipid transport. It has the following features: high hydrophobicity, the ability to bind to the low-density-lipoprotein (LDL) receptor and related receptors, production in various tissues throughout the body, acting as a central apoprotein of cerebrospinal fluid lipoproteins, having three major isoforms (apoE2, apoE3, and apoE4) that vary in their function and susceptibility to genetic mutations¹⁾. Disorders of apoE are associated with atherosclerosis, which causes dyslipidemia and myocardial infarction, and apoE-deficient mice are used as model animals for atherosclerosis^{2, 3)}. In fact, apoE is associated not only with dyslipidemia but also with lipoprotein glomerulopathy, a renal glomerular lesion, and late-onset Alzheimer’s disease (AD). In this review, we summarize the pathophysiology of apoE with a focus on lipid metabolism and review the impact of apoE variants in the pathogenesis of several different diseases except Alzheimer’s disease.

Lipoproteins and ApoE

Proteins that exist in association with lipoproteins are called apolipoproteins (apoproteins). Many apoproteins, including apoE, have an amphipathic α-helix structure. Among apoproteins, apoprotein B100 (apoB100) and the amino terminal 48% of apo B100, which forms apoprotein B48 (apoB48), are very large-molecular-weight proteins. ApoB48 (molecular weight 240 kDa) is found on chylomicrons and chylomicron remnants, whereas apoB100 (molecular weight 500 kDa) is found on very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. A single copy of both apoB forms is present on lipoprotein particles and they do not move between lipoprotein particles. In contrast, multiple copies of apoE and other small apoproteins with molecular weights of 6–50 kDa, such as apoprotein (apo)A-I, A-II, A-V, C-II, and C-III, are present on a single lipoprotein particle and can move between lipoproteins.

When LDL is taken up by cells, apoB100 binds to the LDL receptor as a ligand for uptake. ApoE is the only other ligand that can bind to the LDL receptor. While apoB100 can bind only to the LDL receptor, apoE is a ligand that can bind to many LDL receptor-related receptors and cell surface heparan sulfate proteoglycans (HSPGs), in addition to the LDL receptor⁴⁾.

Function of ApoE

ApoE is a multifunctional protein synthesized and secreted by numerous tissues throughout the body, but hepatocytes contribute to approximately 75% of the apoE peripheral blood pool⁴⁾. Because of the high lipophilicity of apoE, most of it is present on lipoproteins in the blood. In plasma, apoE associates primarily with chylomicrons, chylomicron remnants, VLDL, IDL, and high-density lipoprotein (HDL). One of the main functions of apoE is to mediate lipoprotein clearance through the uptake of remnants (chylomicron and VLDL) and HDL by hepatocytes (Fig.1). The LDL receptor-binding affinity of apoE was reported to be more than 20-fold greater than that of apoB100 ⁵⁾. ApoE binds a wide range of cellular receptors, including the LDL receptor (LDLR), the LDL receptor-related proteins (LRP) LRP1, LRP2, and LRP8, and the very low-density-lipoprotein receptor (VLDLR), which mediate the cellular uptake of the apoE-containing lipoprotein particles⁶⁾. ApoE also exhibits heparin-binding activity and binds HSPGs on the surface of cells, a property that supports the capture and receptor-mediated uptake of apoE-containing lipoproteins by cells⁷⁾. Through its interaction with these receptors and the HSPG-LRP pathway, apoE mediates remnant lipoprotein catabolism (Fig.1). ApoE is involved in the hepatic biosynthesis of VLDLs and their uptake by peripheral tissues, ensuring the delivery of triglycerides and energy storage in muscle, heart, and adipose tissues. ApoE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting⁴⁾.

Fig.1 Schematic diagram of apoE’s function on triglyceride-rich lipoprotein particles or remnant particles inside and outside of blood vessels — ApoE binds to a wide range of cellular receptors, including the LDL receptor (LDLR), LDL receptor-related proteins, and very-low-density lipoprotein receptor (VLDLR), as well as heparan sulfate proteoglycans (HSPG), which mediate the cellular uptake of lipoprotein particles containing apoE. In vessels, meanwhile, apoE on VLDL and chylomicron particles competitively inhibits triglyceride degradation processing by lipoprotein lipase (LPL) promoted by apoC-II and apoA-V. GPIHBP1: glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1, LRP1: LDL receptor-related protein 1.

Structure of ApoE

Human apoE is a protein consisting of 299 amino acid residues with a molecular weight of 34 kDa⁸⁾. ApoE has many amphipathic α-helices (Fig.2). These helices separate the hydrophobic and polar residues into two planes, allowing them to adsorb at polar–nonpolar interfaces such as lipoproteins. ApoE is divided into three structural domains: the N-terminal domain (residues 1–167) with four α-helices (helices 1–4) attached, the hinge domain (residues 168–205) with two helices (residues 168–180 and 190–199), and the C-terminal domain (residues 206–299) with three helices (residues 210–223, 236–266, and 271–276) that binds even more strongly to lipids (Fig.2). The first structural determination of the N-terminal domain of apoE3, reported in 1991, indicated that it is a unique four-α-helix bundle (Fig.2)^{9, 10)}. The structure of the N-terminal domain was subsequently more precisely determined by NMR for apoE3 and by X-ray crystallography for apoE3 and apoE4. As expected, the polar groups in helix 2 (residues 55–79) and the region in helix 4 (residues 131–164) were all shown to be exposed to solvent. Despite extensive analysis, it took 20 years until the whole structure of apoE, including the C-terminal domain, was determined because of its very high affinity for lipids, and the higher-order structure of the full-length protein was first reported in 2011 ¹¹⁾. It was revealed that the C-terminal domain of apoE has three α-helices, which interact with the helices of the N-terminal domain by forming hydrogen bonds and salt bridges. The region of amino acid residues 134–150 of the N-terminal domain helix 4 includes many basic amino acids on its polar face and is important for binding to the LDL receptor (Fig.2). Meanwhile, heparin binding sites are located in both the N-terminal and the C-terminal domains; the heparin binding site in the N-terminal domain is located at residues 142–147, which overlaps with the LDL receptor binding region¹²⁾. In fact, HSPG binding activity is significantly reduced by variants in the basic amino acids Arg142, Arg145, and Lys146, suggesting that these residues contribute to heparin binding. The interaction of apoE with HSPGs may be the first step in the clearance of lipoproteins containing apoE from plasma (Fig.1).

Fig.2. Human apoE model structure with triglyceride-rich lipoprotein particle — ApoE is divided into three structural domains: the N-terminal domain (residues 1–167) with four α-helices (helices 1–4) attached, the hinge domain (residues 168–205) with two helices (residues 168–180 and 190–199), and the C-terminal domain (residues 206–299) that binds even more strongly to lipids. The C-terminal domain of apoE interacts with the helix of the N-terminal domain by forming hydrogen bonds and salt bridges. The region of amino acid residues 134–150 of the N-terminal domain helix 4 contains many basic amino acids on its polar face and is important for binding to the LDL receptor.

Common Isoforms

There are three major isoforms at the APOE locus, ε2, ε3, and ε4, which are generated by the exchange of one amino acid residue at positions 112 and 158 resulting from a single base change (Fig.3). ε3 has Cys112 and Arg158, while ε4 (Cys112Arg, p.Cys130Arg) has arginine at both positions and ε2 (Arg158Cys, p.Arg176Cys) has cysteine at both positions (Fig.3)⁸⁾.

Fig.3. Three major phenotypes (genotypes) of apoE — There are three major isoforms at the APOE locus, namely, ε2, ε3, and ε4, which are generated by the exchange of one amino acid residue at positions 112 and 158, resulting from two single-nucleotide polymorphisms in exon 4.

The combination of these three variants results in three homozygous (ε2ε2, ε3ε3, ε4ε4) and three heterozygous (ε2ε3, ε3ε4, ε4ε2) APOE genotypes. ε3 is the most common APOE genotype in humans, being present in 65%–70% of the population, and is considered the wild type. Meanwhile, ε2 is present in 8%–10% of the population, and ε4 in 15%–20%. The common APOE genotypes can be easily determined by isotyping with the restriction enzyme Hha I¹³⁾. The common isoforms ε2, ε3, and ε4 can be distinguished at the protein level by isoelectric electrophoresis into apoE2, apoE3, and apoE4 (Fig.3)¹⁴⁾. The isoelectric point of many amino acids such as Cys is approximately neutral (pH 5–6), whereas the isoelectric point of Asp or Glu is acidic (pH 3), and that of His, Lys, or Arg is alkaline (pH 8–10). In addition, studies have reported a number of APOE variants (APOE1, E2, E3, E4, E5, E7) that can be detected by isoelectric electrophoresis due to changes in the isoelectric point caused by changes in amino acids. The Cys112Arg and Arg158Cys SNPs appear to be in almost perfect linkage disequilibrium (Fig.3), and the combination of arginine at position 112 and cysteine at position 158, which may define the apoE1, also called apoE3r isoform, is extremely rare¹⁵⁾.

ApoE3 and apoE4 have normal binding activity to the LDL receptor, while apoE2 is defective in such binding (＜2% of the normal activity.) due to the presence of Arg158Cys near the LDL receptor binding site¹⁶⁾. The presence of cysteine at position 158 in ε2 disrupts the normal salt bridging required for the interaction of arginine at position 150 in the receptor binding region with the LDL receptor¹⁷⁾. However, apoE2 retains the ability to bind to HSPG and other related receptors. In the absence of lipid abnormalities, plasma apoE levels are generally reported to tend to be higher for apoE2 and lower for apoE4 ¹⁸⁾.

In contrast, Cys112Arg in apoE4 affects the organization and stability of both the N-terminal and the C-terminal domains and enhances the ability of apoE to bind to lipoproteins. As a result, apoE4 binds better and is more abundant on the surface of VLDL and chylomicron particles than apoE3 or apoE2 ¹⁹⁾.

ApoE is an apoprotein with two sides: intravascular and extravascular. Outside of blood vessels, apoE acts as a ligand, binding to various receptors and causing intracellular uptake of lipoproteins, contributing to lipid lowering (Fig.1). Meanwhile, in vessels, apoE on VLDL and chylomicron particles competitively inhibits triglyceride degradation processing by lipoprotein lipase (LPL) promoted by apoC-II and apoA-V²⁰⁾. Therefore, apoE4, which is abundant on VLDL and chylomicrons, tends to inhibit triglyceride degradation by LPL more readily than apoE2 or apoE3 ²¹⁾.

APOE gene

The APOE gene is located on chromosome 19q.13.32 and forms a very close cluster with APOC1, APOC1 pseudogene, APOC4, and APOC2 (Fig.4). The human APOE gene is located in a region approximately 5000 bp in length and consists of four exons. As shown in Fig.4, the APOE start codon is located in exon 2, and exons 2, 3, and 4 are the regions of the APOE gene encoding the expressed amino acids²²⁾. ApoE is expressed as pre-apoE consisting of 317 amino acid residues; the signal peptide of 18 amino acid residues is cleaved from pre-apoE to produce mature apoE of 299 amino acid residues, which is then secreted (Fig.4).

APOE gene variants have been reported for more than 40 years. Analysis of mutant proteins was also performed in parallel with this work, and thus for a long time APOE gene mutation sites were mostly reported based on the amino acid numbers (n=299) of mature apoE. However, recently, apoE mutational analyses have focused on the gene rather than the protein. In this context, the amino acid number from the universal start codon of the protein, methionine, is often used to represent the mutation site. In this case, the mutation site is always prefixed with “p.” to indicate that the numbering is from the start codon. Because many researchers have been unaware of this, some papers misidentify the number of amino acid residues in apoE, causing previously reported variants to be incorrectly reported as new ones. In the tables of this review, APOE variants are presented using the conventional mature amino acid representation, along with a protein-level “p.” for numbering from the start codon, a base-level “c.,” and a unique “rs” assigned to the SNP site, which is assigned to unique SNP sites. For example, ε4 is rs429358 and ε2 is rs7412. The mutation sites (mutation initiation sites) of Genome Reference Consortium Human (GRCh) Builds 37 and 38 are also listed to facilitate identification by next-generation sequencing (NGS) analysis (Supplementary Table 1).

Supplementary Table 1. Reported APOE variants sorted by DNA sequence.

No.	Variant	Protein sequence change	Genomic change^＊	rs number	Structure	Characteristics	GRCh37	GRCh38	Ref.
1	APOE p.Thr5^＊	p.Trp5Ter	c.15G>A	rs777551553	Signal	FDB	45409896	44906639	39
2	APOE p.Thr11Ala	p.Thr11Ala	c.31A>G	rs144354013	Signal	CHL	45409912	44906655	40
3	APOE p.Thr11Ser	p.Thr11Ser	c.31A>T	rs144354013	Signal	NA	45409912	44906655	127
4	APOE p.Phe12Tyr	p.Phe12Tyr	c.35T>A	rs747078681	Signal	NA	45409916	44906659	127
5	APOE (c.44-1G>C)	NA	c.44-1G>C	NA	Intron 2	HCh	45411016	44907759	40
6	APOE5 (Glu3Lys)	p.Glu21Lys	c.61G>A	rs121918392	N-ter	CHL	45411034	44907777	104,14,107
7	APOE p.Ala23Val (Ala5Val)	p.Ala23Val	c.68C>T	rs776242156	N-ter	NA	45411041	44907784	127
8	APOE4 Philadelphia (Glu13Lys, Arg145Cys)	p.Glu31Lys, p.Arg163Cys	c.91G>A, c.487C>T	rs201672011, rs769455	N-ter	FDB	45411064	44907807	63
9	APOE p.Arg33Cys (Arg15Cys)	p.Arg33Cys	c.97C>T	rs752079771	N-ter	NA	45411070	44907813	127
10	APOE (Trp20Ter)	p.Trp38Ter	c.114G>A	rs2122132512	N-ter	FDB	45411087	44907830	27
11	APOE Kyoto (Arg25Cys)	p.Arg43Cys	c.127C>T	rs121918399	N-ter	LPG	45411100	44907843	87
12	APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg)	p.Leu46Pro, p.Cys130Arg	c.137T>C	rs769452	Helix 1	CHL, AD	45411130	44907873	108,109
13	APOE (Gly31fsTer29/Gly127Asp, Arg158Cys)	p.Gly49fs/ p.Gly145Asp, p.Arg176Cys	c.146Gdel/c.434G>A	rs2122132718	Helix 1	FDB	45411117_9	44907860_2	37,38
14	APOE p.Arg50Cys (Arg32Cys)	p.Arg50Cys	c.148C>T	rs11542029	Helix 1	NA	45411121	44907864	126
15	APOE (Arg32His)/Kyoto (Arg25Cys)	p.Arg50His/ p.Arg43Cys	c.149G>A/c.127C>T	rs762461580/ rs121918399	Helix 1	LPG	45411122	44907865	88
16	APOE p.Thr60Ala (Thr42Ala)	p.Thr60Ala	c.178A>G	rs28931576	Helix 1	NA	45411151	44907894	126
17	APOE p.Ser72Phe (Ser54Phe)	p.Ser72Phe	c.215C>T	rs1969840702	Helix 2	NA	45411188	44907931	127
18	APOE (c.237-33C>G, Arg158Cys)	NA	c.237-33C>G	NA	Intron 3	FDB^＊＊	45411757	44908500	44
19	APOE (c.237-2A>G)	NA	c.237-2A>G	rs397514253	Intron 3	Deficiency, FDB	45411788	44908531	32,33
20	APOE p.Met82Ile (Met64Ile)	p.Met82Ile	c.246G>T	rs557845700	Helix 2	HTG	45411799	44908542	44
21	APOE deficiency (Glu79fsTer98)	p.Glu97fsTer98	c.291del	rs527236160	Helix 2	Deficiency, FDB	45411844	44908587	34
22	APOE5 Frankfurt (Gln81Lys, Cys112Arg)	p.Gln99Lys, p.Cys130Arg	c.295C>A	rs1180612218	Helix 2_3	CHL	45411848	44908591	112
23	APOE5 (Pro84Arg, Cys112Arg)	p.Pro102Arg, p.Cys130Arg	c.305C>G	rs11083750	Helix 2_3	HCh	45411858	44908601	113
24	APOE p.Pro102Leu (Pro84Leu)	p.Pro102Leu	c.305C>T	rs11083750	Helix 2_3	HCh	45411858	44908601	40
25	APOE p.Pro102Gln (Pro84Gln)	p.Pro102Gln	c.305C>A	rs11083750	Helix 2_3	NA	45411858	44908601	126
26	APOE p.Arg108Trip (Arg90Trp)	p.Arg108Trp	c.322C>T	rs1050106163	Helix 3	NL	45411875	44908618	44
27	APOE3 Groningen (Glu96fsTer50)	p.Glu114fsTer50	c.340insG:c.341insG	NA	Helix 3	FDB	45411893	44908636	41
28	APOE p.Glu114Lys (Glu96Lys)	p.Glu114Lys	c.340G>A	rs1169728519	Helix 3	NA	45411893	44908636	127
29	APOE p.Ala117Thr (Ala99Thr)	p.Ala117Thr	c.349G>A	rs28931577	Helix 3	NA	45411902	44908645	126
30	APOE p.Arg121Trp (Arg103Trp)	p.Arg121Trp	c.361C>T	rs11542037	Helix 3	FDB	45411914	44908657	44
31	APOE4 (Cys112Arg)	p.Cys130Arg	c.388T>C	rs429358	Helix 3	Common	45411941	44908684
32	APOE Tsukuba (Arg114Cys)	p.Arg132Cys	c.394C>T	rs11542041	Helix 3	LPG	45411947	44908690	86
33	APOE p.Arg132Ser (Arg114Ser)	p.Arg132Ser	c.394C>A	rs11542041	Helix 3	NA	45411947	44908690	126
34	APOE Arg114Pro	p.Arg132Pro	c.395G>C	rs1263042140	Helix 3	HCh	45411948	44908691	43
35	APOE p.Tyr136His (Tyr118His)	p.Tyr136His	c.406T>C	rs1969862344	Helix 3	NL	45411959	44908702	44
36	APOE p.Arg137Cys (Arg119Cys)	p.Arg137Cys	c.409C>T	rs573658040	Helix 3	FH	45411962	44908705	40
37	APOE p.Arg137His (Arg119His)	p.Arg137His	c.410G>A	rs11542035	Helix 3	FH	45411963	44908706	40
38	APOE p.Glu139Val (Glu121Val)	p.Glu139Val	c.416A>T	rs41382345	Helix 3	NA	45411969	44908712	126
39	APOE3 Leiden (121-127dupGluValGlnAlaM etLeuGly)	p.139_145dup	c.415_435dup	rs397514254	Helix 3_4	dFDB	45411964	44908707	55
40	APOE1 (Gly127Asp, Arg158Cys)	p.Gly145Asp, p.Arg176Cys	c.434G>A	rs267606664	Helix 3_4	FDB	45411987	44908730	56,57
41	APOE p.Glu150Gly (Glu132Gly)	p.Glu150Gly	c.449A>G	rs11542034	Helix 4	NA	45412002	44908745	126
42	APOE p.Arg152Gln (Arg134Gln)	p.Arg152Gln	c.455G>A	rs28931578	Helix 4	NA	45412008	44908751	126
43	APOE5 (Val135_Arg142dup)	p.Val153_Arg160dup	c.457_480dup24	NA	Helix 4	HTG	45412010	44908753	114
44	APOE 136fsTer96	p.Arg154fsTer96	c.460Cdel	rs121918393	Helix 4	FDB	45412013	44908756	42
45	APOE2 Heidelberg (Arg136Cys)	p.Arg154Cys	c.460C>T	rs121918393	Helix 4	dFDB	45412013	44908756	47
46	APOE2 Christchurch (Arg136Ser)	p.Arg154Ser	c.460C>A	rs121918393	Helix 4	dFDB, CHL	45412013	44908756	26,48
47	APOE3’ (Arg136His)	p.Arg154His	c.461G>A	rs200703101	Helix 4	FDB	45412014	44908757	59
48	APOE p.Leu155Phe (Leu137Phe)	p.Leu155Phe	c.463 C>T	rs1018669382	Helix 4	FH	45412016	44908759	40
49	APOE Tokyo/Maebashi (141-143del:143- 145del)	p.159_161del:p.161- 163del	c.475_483del9: c.480_488del9	NA	Helix 4	LPG	45412033	44908776	73,74
50	APOE3 (Arg142Cys)	p.Arg160Cys	c.478C>T	rs387906567	Helix 4	dFDB	45412031	44908774	49,50
51	APOE1 Nagoya (Arg142Ser, Arg158Cys)	p.Arg160Ser, p.Arg176Cys	c.478C>A	rs387906567	Helix 4	FDB	45412031	44908774	60
52	APOE2 (Arg142Leu)	p.Arg160Leu	c.479G>T	rs1452005331	Helix 4	dFDB	45412032	44908775	51
53	APOE 15 bp deletion (142-146del)	p.160_164del	c.477_491del15	NA	Helix 4	LPG	45412033	44908776	75
54	APOE p.Lys161Asn (Lys143Asn)	p.Lys161Asn	c.483G>T	rs867215645	Helix 4	NA	45412036	44908779	127
55	APOE2 (Arg145Cys)	p.Arg163Cys	c.487C>T	rs769455	Helix 4	FDB, FH	45412040	44908783	64,65,57
56	APOE Kochi (Arg145His)	p.Arg163His	c.488G>A	rs121918397	Helix 4	FDB	45412041	44908784	61,62
57	APOE Sendai (Arg145Pro)	p.Arg163Pro	c.488G>C	rs121918397	Helix 4	LPG	45412041	44908784	72
58	APOE2 (Lys146Gln)	p.Lys164Gln	c.490A>C	rs121918394	Helix 4	dFDB, AD	45412043	44908786	45
59	APOE1 Harrisburg (Lys146Glu)	p.Lys164Glu	c.490A>G	rs121918394	Helix 4	dFDB	45412043	44908786	52,53
60	APOE1 Hammersmith (Lys146Asn, Arg147Trp)	p.Lys164Asn, p.Arg165Trp	c.492G>C, c.493C>T	rs1446645173, rs1402219759	Helix 4	dFDB	45412045_6	44908788_9	54
61	APOE p.Arg165Trp (Arg147Trip)	p.Arg165Trp	c.493C>T	rs1402219759	Helix 4	FDB	45412046	44908789	44
62	APOE Chicago (Arg147Pro)	p.Arg165Pro	c.494G>C	rs1332591068	Helix 4	LPG	45412047	44908790	76
63	APOE p.Leu167del (Leu149del)	p.Leu167del	c.499_501delCTC: c.500_502delTCC	rs515726148	Helix 4	FH	45412049	44908792	115,116,117
64	APOE Okayama (Arg150Gly)	p.Arg168Gly	c.502C>G	rs867594573	Helix 4	LPG	45412055	44908798	77
65	APOE Modena (Arg150Cys)	p.Arg168Cys	c.502C>T	rs867594573	Helix 4	LPG	45412055	44908798	78
66	APOE Guangzhou (Arg150Pro)	p.Arg168Pro	c.503G>C	rs376170967	Helix 4	LPG	45412056	44908799	79
67	APOE (Arg150His)	p.Arg168His	c.503G>A	rs376170967	Helix 4	NL	45412056	44908799	43
68	APOE2 Kanto (Asp151dupAsp)	p.Asp169dupAsp	c.505_507insGAT:c.508_510insGAT	NA	Helix 4	LPG	45412058	44908801	70,80
69	APOE Las Vegas (Ala152Asp)	p.Ala170Asp	c.509C>A	rs1969869057	Helix 4	LPG	45412062	44908805	81
70	APOE Chengdu (Leu155Pro)	p.Leu173Pro	c.518T>C	NA	Helix 4	LPG	45412071	44908814	82
71	APOE1 (156_173del)	p.174_191del	c.520_573del	NA	Helix 4	LPG	45412073	44908816	83
72	APOE2 (Arg158Cys)	p.Arg176Cys	c.526C>T	rs7412	Helix 4	Common	45412079	44908822
73	APOE Osaka/Kurashiki (Arg158Pro)	p.Arg176Pro	c.527G>C	NA	Helix 4	LPG	45412080	44908823	84,85
74	APOE p.Val179Ala (Val161Ala)	p.Val179Ala	c.536T>C	rs1421977676	Helix 4	CHL	45412089	44908832	40
75	APOE (Ala166fs)	p.Ala184fs	c.550Gdel	NA	Helix 4_ hinge	HTG	45412103	44908846	43
76	APOE p.Glu189Lys (Glu171Lys)	p.Glu189Lys	c.565G>A	rs11542032	Hinge	NA	45412118	44908861	126
77	APOE p.Gly191Cys (Gly173Cys)	p.Gly191Cys	c.571G>T	rs1265472491	Hinge	HCh	45412124	44908867	44
78	APOE1 Baden (Arg180Cys, Arg158Cys)	p.Arg198Cys, p.Arg176Cys	c.592C>T	rs1426426514	Hinge	HTG	45412145	44908888	119
79	APOE2 Toranomon (Gln187Glu)	p.Gln205Glu	c.613C>G	rs2122138444	Hinge	FDB	45412166	44908909	66,67
80	APOE p.Gln205Arg (Gln187Arg)	p.Gln205Arg	c.614A>G	rs11542030	Hinge	NA	45412167	44908910	126
81	APOE p.Ala210Ser (Ala192Ser)	p.Ala210Ser	c.628G>T	NA	Hinge	NA	45412181	44908924	127
82	APOE p.Val213Glu (Val195Glu)	p.Val213Glu	c.638T>A	rs1227709957	Hinge	FH	45412191	44908934	40
83	APOE Toyonaka (Ser197Cys, Arg158Cys)	p.Ser215Cys, p.Arg176Cys	c.644C>G	rs11542027	Hinge	GP	45412197	44908940	101
84	APOE p.Ser215Phe (Ser197Phe)	p.Ser215Phe	c.644C>T	rs11542027	Hinge	NA	45412197	44908940	127
85	APOE p.Gly218Cys (Gly200Cys)	p.Gly218Cys	c.652G>T	rs1488379910	Hinge	FH	45412205	44908948	40
86	APOE p.Gly218Ser (Gly200Ser)	p.Gly218Ser	c.652G>A	rs1488379910	Hinge	NA	45412205	44908948	127
87	APOE p.Pro220Leu (Pro202Leu)	p.Pro220Leu	c.659C>T	rs1265743589	Hinge	CHL	45412212	44908955	44
88	APOE5 (Gln204Lys, Cys112Arg)	p.Gln222Lys, p.Cys130Arg	c.664C>A	rs1181840153	Hinge	NL	45412217	44908960	125
89	APOE 10 bp deletion (Ala209GlyfsTer20)	p.Ala227fsTer20	c.679_688del	NA	C-ter	Deficiency, FDB	45412232	44908975	35
90	APOE3 Washington (Trp210Ter)	p.Trp228Ter	c.683G>A	rs121918396	C-ter	Deficiency, FDB	45412236	44908979	36
91	APOE5 (Glu212Lys)	p.Glu230Lys	c.688G>A	rs567353589	C-ter	NL	45412241	44908984	124,125
92	APOE (Arg217Trp)	p.Arg235Trp	c.703C>T	rs530010303	C-ter	FH	45412256	44908999	29
93	APOE2 Fukuoka (Arg224Gln)	p.Arg242Gln	c.725G>A	rs267606663	C-ter	FH	45412278	44909021	120
94	APOE2 Dunedin (Arg228Cys)	p.Arg246Cys	c.736C>T	rs121918395	C-ter	HTG	45412289	44909032	121
95	APOE Hong Kong (Asp230Tyr)/Kyoto (Arg25Cys)	p.Asp248Tyr/ p.Arg43Cys	c.742G>T	NA/ rs121918399	C-ter	LPG	45412298	44909038	89
96	APOE p.Glu249Lys (Glu231Lys)	p.Glu249Lys	c.745G>A	rs762906934	C-ter	CHL	45412298	44909041	40
97	APOE p.Glu252Lys (Glu234Lys)	p.Glu252Lys	c.754G>A	NA	C-ter	CHL	45412307	44909050	40
98	APOE2 (Val236Glu)	p.Val254Glu	c.761T>A	rs199768005	C-ter	CHL	45412314	44909057	122
99	APOE7 Suita (Glu244Lys, Glu245Lys)	p.Glu262Lys, p.Glu263Lys	c.784G>A, c.787G>A	rs140808909, rs190853081	C-ter	CHL	45412337	44909080	123,14
100	APOE3 (Arg251Gly, Cys112Arg)	p.Arg269Gly, p.Cys130Arg	c.805C>G	rs267606661	C-ter	CHL	45412358	44909101	122
101	APOE1 (Leu252Glu, Arg158Cys)	p.Leu270Glu, p.Arg176Cys	c.808C>G, c.809T>A	rs992440908, NA	C-ter	HCh	45412361_2	44909104_5	122
102	APOE4’ (Arg274His, Cys112Arg)	p.Arg292His, p.Cys130Arg	c.875G>A	rs121918398	C-ter	NL	45412428	44909171	122
103	APOE p.Val305Met (Val287Met)	p.Val305Met	c.913G>A	rs749102800	C-ter	NA	45412466	44909209	127
104	APOE4 (Ser296Arg)	p.Ser314Arg	c.940A>C	rs28931579	C-ter	NL	45412493	44909236	122

Open in a new tab

^＊: Main mutation sites are shown, ^＊＊: There was linkage disequilibrium with apoE2, resulting in FDB in apoE2 homozygotes, GRCh37: Genome Reference Consortium Human Build 37, GRCh38: Genome Reference Consortium Human Build 38, Ref.: references, NA: not available, Signal: signal peptide, N-ter: N-terminal domain, Hinge: hinge domain, C-ter: C-terminal domain, Common: common isoforms, FDB: familial dysbetalipoproteinemia (familial type III HLP), dFDB: autosomal dominant familial dysbetalipoproteinemia (familial type III HLP), FH: familial hypercholesterolemia including autosomal dominant hypercholesterolemia (ADH) and severe familial type III HLP, HCh: hypercholesterolemia, HTG: hypertriglyceridemia, CHL: combined hyperlipidemia, AD: Alzheimer’s disease, NL: no lipid abnormalities

Familial Type III Hyperlipoproteinemia (HLP)

Familial type III HLP is also called familial dysbetalipoproteinemia (FDB). It is a metabolic disorder that results in increased cholesterol and triglyceride-rich lipoproteins termed β-VLDL, owing to their β-electrophoretic migration instead of the usual pre-β migration of typical VLDL. Patients with familial type III HLP are known to be susceptible to the early development of atherosclerosis. Clinical manifestations of familial type III HLP can include tuberous or planar xanthomas of the skin or tendon sheath xanthomas, as well as early-onset coronary artery disease. Familial type III HLP is caused by the accumulation of chylomicron remnants derived from intestinal lipoproteins and VLDL remnants derived from hepatic lipoproteins; these abnormal cholesterol, triglyceride, and apoE-enriched lipoproteins, collectively termed β-VLDL, are the diagnostic features of this disease. The definition and diagnostic details of familial type III HLP are discussed in other review articles^23-25). Usually, in familial type III HLP, plasma cholesterol and triglycerides are almost equally elevated above 300 mg/dL. The primary molecular cause of familial type III HLP is the presence of the homozygous form of APOE2 (Arg158Cys), an LDL receptor binding-deficient isoform of apoE, which is associated with the recessive inheritance of the disease. In fact, more than 90% of affected individuals are APOE2 homozygotes, with the remainder having rare APOE variants, including those causing apoE deficiency or compound heterozygotes of APOE variants and APOE2 ^23, ^25-28). However, less than 10% of APOE2 homozygotes develop type III HLP, and most APOE2/E2 carriers are either normolipidemic or hypocholesterolemic. Thus, additional genetic, hormonal, or environmental factors such as obesity, hypothyroidism, estrogen status, and diabetes are necessary for the development of familial type III HLP. Familial type III HLP is more common and tends to develop earlier in men than in women, in whom it rarely occurs until after menopause. As the diagnosis of type III HLP requires analysis of lipoproteins and apoE, measurement of serum cholesterol and triglyceride levels alone often leads to the diagnosis of familial hypercholesterolemia (FH), combined hyperlipidemia (CHL), or hypertriglyceridemia. Relatively few cases of familial type III HLP are correctly diagnosed as type III because of their good response to lipid-lowering drugs and the difficulty of achieving an accurate diagnosis²⁸⁾.

APOE Deficiency

Severe type III HLP meets the criteria for FH. FH is caused primarily by variants in the LDLR gene. Other FH-causing genes include proprotein convertase subtilisin kexin 9 (PCSK9), low-density-lipoprotein receptor adapter protein 1 (LDLRAP1), APOB, and APOE. Genetic variants in LDLR, PCSK9, and APOB cause autosomal dominant hypercholesterolemia (ADH), while pathogenic variants in LDLRAP1 cause recessive FH. FH due to APOE deficiency is recessively inherited, as in APOE-deficient homozygotes, but APOE variants diagnosed as ADH have also been reported²⁹⁾.

To date, 13 different APOE deficiencies have been reported. Of these, the two early studies of complete APOE deficiency only involved analysis at the protein level and the site of mutation was not reported^{30, 31)}. Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes^{27, 29-40)}.

Two cases with no reported mutation site and homozygotes for APOE deficiency due to variant in the intron 3 acceptor site (c.237-2A>G)^{32, 33)} and APOE deficiency (Glu79fsTer98)³⁴⁾ with almost no detectable apoE have been reported to cause severe type III HLP, including various xanthomas as well as palmar linear xanthomas (Table 1). Homozygotes for the APOE 10-bp deletion (Ala209GlyfsTer20), in which 19 amino acids from among the 209 amino acids at the C-terminus were nonfunctional, also exhibited severe familial type III HLP³⁵⁾. Meanwhile, homozygotes for APOE3 Washington (Trp210Ter) showed relatively mild type III HLP, possibly due to the structure of apoE retaining the N-terminal side (Table 1)³⁶⁾. Plasma lipid and lipoprotein cholesterol values of two heterozygous offspring were found to be within the normal range.

Table 1. List of APOE deficiencies.

Variant	No.	Protein sequence change	Genomic change^＊	rs number	Exon/intron	Protein structure	Homo/hetero	Characteristics	Ref.
1	APOE p.Thr5^＊	p.Thr5Ter	c.15G>A	rs777551553	Exon 2	Signal	Hetero	FDB	39
2	APOE (c.44-1G>C)	NA	c.44-1G>C	NA	Intron 2	NA	Hetero	HCh	40
3	APOE (Trp20Ter)	p.Trp38Ter	c.114G>A	rs2122132512	Exon 3	N-ter	Hetero	FDB	27
4	APOE (Gly31fsTer29/Gly127Asp, Arg158Cys)	p.Gly49fs/ p.Gly145Asp, p.Arg176Cys	c.146Gdel/c.434G>A	rs2122132718	Exon 3	Helix 1	Compound	FDB	37,38
5	APOE (c.237-2A>G)	NA	c.237-2A>G	rs397514253	Intron 3	NA	Homo	Deficiency, FDB	32,33
6	APOE deficiency (Glu79fsTer98)	p.Glu97fsTer98	c.291Gdel	rs527236160	Exon 4	Helix 2	Homo	Deficiency, FDB	34
7	apoE3 Groningen (Glu96fsTer50)	p.Glu114fsTer50	c.340insG:c.341insG	NA	Exon 4	Helix 3	Hetero	FDB	41
8	APOE 136fsTer96	p.Arg154fsTer96	c.460Cdel	rs121918393	Exon 4	Helix 4	Hetero	FDB	42
9	APOE (Ala166fs)	p.Ala184fs	c.550Gdel	NA	Exon 4	Helix 4_ hinge	Hetero	HTG	43
10	APOE 10 bp deletion (Ala209GlyfsTer20)	p.Ala227fsTer20	c.679_688del	NA	Exon 4	C-ter	Homo	Deficiency, FDB	35
11	APOE Washington (Trp210Ter)	p.Trp228Ter	c.683G>A	rs121918396	Exon 4	C-ter	Homo	Deficiency, FDB	36
	APOE (c.237-33C>G, Arg158Cys)	NA	c.237-33C>G	NA	Intron 3	NA	Hetero	FDB^＊＊	44

Open in a new tab

Ref.: references, NA: not available, Homo: homozygote, Hetero: heterozygote, Compound: compound heterozygote, Signal: signal peptide, N-ter: N-terminal domain, hinge: hinge domain, C-ter: C-terminal domain, hinge: hinge domain, FDB: familial dysbetalipoproteinemia (familial type III HLP), ^＊: Main mutation sites are shown, ^＊＊: There was linkage disequilibrium with apoE2, resulting in FDB in apoE2 homozygotes, HCh: hypercholesterolemia, HTG: hypertriglyceridemia, Deficiency: apoE deficiency

In heterozygotes with APOE deficiency, when the mutant apoE was absent or dysfunctional, the nature of the apoE of the remaining allele affected the manifestation of familial type III HLP, with some cases showing type III HLP and others showing no lipid abnormalities. A 60-year-old Caucasian male compound heterozygous for APOE1 (Gly127Asp, Arg158Cys) and a nucleotide deletion of guanosine at codon 31 (Gly31fsTer29) was reported to have a severe form of familial type III HLP (Table 1)^{37, 38)}. In family studies, normal to mild dyslipidemia was reported when the remaining allele was apoE3, while type III HLP was reported when it was APOE2. Heterozygous APOE (p.Thr5*) was found in two families in a screening of a hypercholesterolemic, hypertriglyceridemic population in Norway³⁹⁾. APOE (p.Thr5*) does not express apoE because the fifth position of the signal peptide is a stop codon. In one family, only two of the five carriers of the APOE2 allele showed type III HLP. Meanwhile, in the second family, the five carriers did not have the APOE2 allele and did not have type III HLP. Heterozygous APOE (c.44-1G>C) was recently discovered in the screening of hypercholesterolemic patients in a French cohort⁴⁰⁾. APOE (c.44-1G>C) involves a mutation of the intron 2 acceptor site and apoE is not expressed from this allele, but no details were available other than that the case involved hypercholesterolemia. Elsewhere, APOE (Trp20Ter) was detected by phenotypic and genotypic analyses of apoE in German type III HLP cases²⁷⁾. In a study of a single family, only one of the three APOE (Trp20Ter) carriers with the APOE2 allele had hypertriglycemia, while the two with the E3 allele were normolipidemic. APOE Groningen (Glu96fsTer50) was identified as a mutation in which a G was inserted in codon 95 or 96 (95AAG96GAG>95AAG96GGA-G) of the APOE3 allele⁴¹⁾. APOE Groningen (Glu96fsTer50) was detected in the analysis of a type III HLP case. Five APOE Groningen (Glu96fsTer50) carriers were detected in a family study, of which only three cases with the E2 allele, including the proband, exhibited type III HLP. Heterozygosity for APOE (136fsTer96) was also found in an Indigenous Australian woman⁴²⁾. She had the E2 allele and was diagnosed with type III HLP, while a case with APOE (136fsTer96) heterozygosity along with the E4 allele was normolipidemic. In addition, a case heterozygous for APOE (Ala166fs) was discovered upon screening diabetic patients in the United Kingdom⁴³⁾. APOE (Ala166fs) showed E2 on isoelectric electrophoresis, while the other allele was E3 and was not associated with hyperlipidemia.

Another example of an APOE variant, APOE (c.237-33C>G), recently reported in Spain, is a mutation adjacent to the splicing branchpoints of intron 3, which might impair splicing⁴⁴⁾. However, it was found to be in linkage disequilibrium with APOE2 (Arg158Cys) and only two of the four reported cases, where the other allele was also E2, had type III HLP, while the other two had CHL.

Familial type III HLP not due to APOE2 Homozygotes

Approximately 10% of patients with familial type III HLP have other APOE variants or APOE deficiency. Some of these rare APOE variants that cause familial type III HLP were found to exhibit a dominant mode of inheritance^45, ⁴⁶⁾. In these cases, a single defective APOE allele is usually sufficient to cause hyperlipidemia. A secondary factor promoting the accumulation of these residual dominant type III HLPs has been reported to exist in helix 4 of the N-terminal domain (Fig.2, Fig.5). These type III HLPs are highly penetrant dominant traits. Rare APOE variants associated with dominant type III HLPs include single-nucleotide substitutions at APOE2 Heidelberg (Arg136Cys)⁴⁷⁾, APOE2 Christchurch (Arg136Ser)^{26, 48)}, APOE2 (Arg142Cys)^{49, 50)}, APOE2 (Arg142Leu)⁵¹⁾, APOE2 (Lys146Gln)⁴⁵⁾, and APOE1 Harrisburg (Lys146Glu)^{52, 53)} (Table 2, Fig.5). In addition, APOE1 Hammersmith (Lys146Asn, Arg147Trp)⁵⁴⁾ and amino acid 121–127 tandem repeat insertions (APOE3 Leiden)⁵⁵⁾ have been reported as causative of dominantly inherited type III HLP (Table 2). APOE p.Arg121Trp (Arg103Trp) and APOE p.Arg165Trp (Arg147Trp) have also recently been reported to cause type III HLP, but only in one case each, and it was not known whether they were dominant⁴⁴⁾.

Fig.5. Schematic representation of APOE variants with familial type III HLP (top) and LPG (bottom) — Variants that cause both familial type III HLP and LPG are concentrated in the LDL receptor binding region (amino acids 136–150). However, variants causing type III HLP do not cause lipoprotein glomerulopathy and present different pathologies from each other. ^＊: non-dominant familial type III HLP.

Table 2. Variants of familial type III HLP not due to APOE2 homozygotes or APOE deficiency.

No.	Variant	Protein sequence change	Genomic change^＊	rs number	Protein structure	ApoE phenotypes	Characteristics	gnomAD/ TOPMed^＃ frequency	Ref.
1	APOE p.Arg121Trp (Arg103Trp)	p.Arg121Trp	c.361C>T	rs11542037	Helix 3	NA	FDB	0.000005	44
2	APOE Leiden (121-127dup GluValGlnAlaMetLeuGly)	p.139_145dup	c.415_435dup	rs397514254	Helix 3_4	E3	dFDB	NA	55
3	APOE1 (Gly127Asp, Arg158Cys)	p.Gly145Asp, p.Arg176Cys	c.434G>A	rs267606664	Helix 3_4	E1	FDB	0.00015300	56,57
4	APOE Heidelberg (Arg136Cys)	p.Arg154Cys	c.460C>T	rs121918393	Helix 4	E2	dFDB	0.00008980	47
5	APOE Christchurch (Arg136Ser)	p.Arg154Ser	c.460C>A	rs121918393	Helix 4	E3	dFDB, CHL	0.00001280	26,48
6	APOE3’ (Arg136His)	p.Arg154His	c.461G>A	rs200703101	Helix 4	E4	FDB	NA	59
7	APOE2 (Arg142Cys)	p.Arg160Cys	c.478C>T	rs387906567	Helix 4	E3	dFDB	0.000006	49,50
9	APOE Nagoya (Arg142Ser, Arg158Cys)	p.Arg160Ser, p.Arg176Cys	c.478C>A	rs387906567	Helix 4	E1	FDB	NA	60
8	APOE2 (Arg142Leu)	p.Arg160Leu	c.479G>T	rs1452005331	Helix 4	E2	dFDB	NA	51
10	APOE2 (Arg145Cys)	p.Arg163Cys	c.487C>T	rs769455	Helix 4	E2	FDB, FH	0.00211000	64,65,57
10_1	APOE Philadelphia (Glu13Lys, Arg145Cys)	p.Glu31Lys, p.Arg163Cys	c.91G>A, c.487C>T	rs201672011, rs769455	Helix 4	E4	FDB	0.00013200	63
11	APOE Kochi (Arg145His)	p.Arg163His	c.488G>A	rs121918397	Helix 4	E3	FDB	0.00000648	61,62
12	APOE2 (Lys146Gln)	p.Lys164Gln	c.490A>C	rs121918394	Helix 4	E2	dFDB, AD	0.00000651	45
13	APOE Harrisburg (Lys146Glu)	p.Lys164Glu	c.490A>G	rs121918394	Helix 4	E1	dFDB	0.000007	52,53
14	APOE1 Hammersmith (Lys146Asn, Arg147Trp)	p.Lys164Asn, p.Arg165Trp	c.492G>C, c.493C>T	rs1446645173, rs1402219759	Helix 4	E1	dFDB	NA	54
15	APOE p.Arg165Trp (Arg147Trp)	p.Arg165Trp	c.493C>T	rs1402219759	Helix 4	NA	FDB	0.000004^#	44
16	APOE2 Toranomon (Gln187Glu)	p.Gln205Glu	c.613C>G	rs2122138444	Hinge	E2	FDB	NA	66,67

Open in a new tab

^＊: Main mutation sites are shown, gnomAD: Genome Aggregation Database, TOPMed: Trans-Omics for Precision Medicine, ^＃: TOPMed frequency, Ref.: references, NA: not available, Hinge: hinge domain, FDB: familial dysbetalipoproteinemia (familial type III HLP), dFDB: autosomal dominant familial dysbetalipoproteinemia (familial type III HLP), CHL: combined hyperlipidemia, FH: familial hypercholesterolemia, AD: Alzheimer’s disease

The Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys)^{26, 38, 56, 57)}. This variant is not causative of a dominantly inherited familial type III HLP and is not directly related to receptor binding, but may be one of the factors that cause hyperlipidemia in association with the ε2 allele^{26, 58)}. Nine carriers (all heterozygotes) of APOE3’ (Arg136His) were reported to have levels of very low-density-lipoprotein (VLDL) cholesterol and triglycerides twice as high as those of nine noncarriers⁵⁹⁾. APOE3’ (Arg136His) might be associated with recessive expression of type III HLP. Meanwhile, APOE1 Nagoya (Arg142Ser, Arg158Cys) was reported from a case of familial hypercholesterolemia and type III HLP, occurring in an apoE2 homozygote⁶⁰⁾. Only one case of this kind was reported, and it was unclear whether it involved dominant type III HLP. Moreover, APOE3 Kochi (Arg145His) was reported to exhibit type III HLP, but this was not a highly penetrant dominant trait^{61, 62)}. Some APOE3 Kochi (Arg145His) carriers have also been reported to have normal lipid levels or hypertriglyceridemia. Furthermore, severe type III HLP has been reported in APOE4 Philadelphia (Glu13Lys, Arg145Cys) homozygotes⁶³⁾, while APOE (Arg145Cys) heterozygotes in Africa-derived populations were associated with higher triglyceride levels⁶⁴⁾. APOE (Arg145Cys) was inherited dominantly with incomplete penetrance and was thought to be dependent on environmental factors^{64, 65)}. APOE (Arg145Cys) homozygote was also found in a cohort of autosomal dominant hypercholesterolemia (ADH) patients in France⁵⁷⁾. Finally, APOE2 Toranomon (Gln187Glu) located in the hinge region was found in association with the recessive expression of type III HLP with coronary atherosclerosis^{66, 67)}.

Lipoprotein Glomerulopathy (LPG)

LPG is a rare renal disease first reported in Japan in 1989 ⁶⁸⁾. Since then, over 150 cases have been reported, primarily in East Asia, especially in Japan and China, but also from other regions of the world. LPG is characterized by dilated glomerular capillaries with lipoprotein clots showing lamellar formation, as seen on renal biopsy⁶⁹⁾.

LPG was initially identified as a glomerular disease associated with type III HLP⁶⁸⁾. However, its genetics and pathology differ from those of apoE2 homozygote glomerulopathy, which causes type III HLP. The renal involvement in apoE2 homozygote glomerulopathy is thought to follow the mechanism of atherosclerosis, with mesangial cells and macrophages infiltrating the mesangial space taking up lipoproteins and contributing to the development of glomerulosclerosis. In contrast to apoE2 homozygote glomerulopathy, LPG is characterized by dilation of glomerular capillaries with lipoprotein thrombi showing lamellar formation, directly inducing glomerular damage without inducing foamy changes⁶⁸⁾.

Clinically, LPG was found to be associated with several distinctive features, including proteinuria and dyslipidemia. LPG-induced kidney damage gradually progresses to end-stage renal failure. While proteinuria may start out mild, it frequently progresses to nephrotic syndrome⁶⁹⁾. LPG is more seen in men and is often familial in nature. The dyslipidemia seen in LPG is similar to type III HLP, with elevated levels of serum triglycerides and apoE. Unlike in type III HLP, however, patients with LPG do not develop palmar linear xanthomas or tendon xanthomas, and they have a low risk of complications related to atherosclerosis⁷⁰⁾. Prevention of hypertriglyceridemia may be important in LPG therapy, and the efficacy of fibrates, including fenofibrate, has been reported in several cases in Japan and China. Hu et al. compared patient and kidney survival over 3 years between fenofibrate-treated and control groups, confirming the value of fenofibrate in LPG treatment⁷¹⁾.

APOE gene variants have been identified in nearly all cases of LPG, which is considered to be an inherited disease caused by the accumulation of abnormal lipoproteins containing mutant apoE in the glomeruli.

The first APOE variant associated with LPG was reported in Japan and is known as APOE Sendai (Arg145Pro)⁷²⁾. To date, 14 different variants in the APOE gene have been reported as causes of LPG (Fig.5, Table 3). Most were heterozygous apoE missense variants close to the LDL receptor binding site.

Table 3. Variants of LPG and APOE Toyonaka.

No.	Variant	Protein sequence change	Genomic change^＊	rs number	Protein structure	ApoE phenotypes	Characteristics	gnomAD/ TOPMed^＃ frequency	Ref.
1	APOE Kyoto (Arg25Cys)	p.Arg43Cys	c.127C>T	rs121918399	N-ter	E2	LPG	0.00000799	87
1_1	APOE Kyoto (Arg25Cys)/ (Arg32His)	p.Arg43Cys/ p.Arg50His	c.127C>T/c.149G>A	/ rs762461580	N-ter	NA	LPG	/ 0.000015^＃	88
1_2	APOE Kyoto (Arg25Cys)/ Hong Kong (Asp230Tyr)	p.Arg43Cys/ p.Asp248Tyr	c.127C>T/c.742G>T	/ NA	N-ter	NA	LPG	/ NA	89
2	APOE Tsukuba (Arg114Cys)	p.Arg132Cys	c.394C>T	rs11542041	Helix 3	E2	LPG	0.00006390	86
3	APOE Tokyo/Maebashi (141-143del:143-145del)	p.159_161del:p.161- 163del	c.475_483del9:c.480_488del9	NA	Helix 4	E1	LPG	NA	73,74
4	APOE 15 bp deletion (142- 146del)	p.160_164del	c.477_491del15	NA	Helix 4	NA	LPG	NA	75
5	APOE Sendai (Arg145Pro)	p.Arg163Pro	c.488G>C	rs121918397	Helix 4	E2	LPG	0.000006	72
6	APOE Chicago (Arg147Pro)	p.Arg165Pro	c.494G>C	rs1332591068	Helix 4	E2	LPG	NA	76
6_1	APOE Chicago (Arg147Pro)/ E5(Glu3Lys)	p.Arg165Pro/ p.Glu21Lys	c.494G>C/c.61G>A	rs1332591068	Helix 4	E4	LPG	/ 0.000007	90
7	APOE Okayama (Arg150Gly)	p.Arg168Gly	c.502C>G	rs867594573	Helix 4	E2	LPG	NA	77
8	APOE Modena (Arg150Cys)	p.Arg168Cys	c.502C>T	rs867594573	Helix 4	E2	LPG	NA	78
9	APOE Guangzhou (Arg150Pro)	p.Arg168Pro	c.503G>C	rs376170967	Helix 4	E2	LPG	0.000137	79
10	APOE Kanto (Asp151dupAsp)	p.Asp169dupAsp	c.505_507insGAT:c.508_510insGAT	NA	Helix 4	E2	LPG	NA	70,80
11	APOE Las Vegas (Ala152Asp)	p.Ala170Asp	c.509C>A	rs1969869057	Helix 4	E2	LPG	NA	81
12	APOE Chengdu (Leu155Pro)	p.Leu173Pro	c.518T>C	NA	Helix 4	E3	LPG	NA	82
13	APOE1 (156_173del)	p.174_191del	c.520_573del	NA	Helix 4	E1	LPG	NA	83
14	APOE Osaka/Kurashiki (Arg158Pro)	p.Arg176Pro	c.527G>C	NA	Helix 4	E2	LPG	NA	84,85
	APOE Toyonaka (Ser197Cys, Arg158Cys)	p.Ser215Cys, p.Arg176Cys	c.644C>G	NA	Hinge	E2	GP	NA	101

Open in a new tab

Seven of these variants, APOE Tokyo/Maebashi (141–143del or 142–144del)^{73, 74)}, APOE 15bp deletion (142–146del)⁷⁵⁾, and single-nucleotide substitutions of Arg145, Arg147, and Arg150, APOE-Sendai (Arg145Pro)⁷²⁾, APOE Chicago (Arg147Pro)⁷⁶⁾, APOE Okayama (Arg150Gly)⁷⁷⁾, APOE Modena (Arg150Cys)⁷⁸⁾, and APOE Guangzhou (Arg150Pro)⁷⁹⁾, are in the LDL receptor binding site of helix 4 of the N-terminal domain (Fig.2, Fig.5, Table 3). The causative APOE variants in LPG were often found in the LDL receptor binding site of helix 4, similar to the causative APOE mutation sites in familial type III HLP, but the same variant did not appear to cause LPG and familial type III HLP.

Five variants in helix 4 that were not in the LDL receptor binding site were identified (Fig.5), but were reported to cause LPG, namely, APOE Kanto (Asp151dupAsp)^{70, 80)}, APOE Las Vegas (Ala152Asp)⁸¹⁾, APOE Chengdu (Leu155Pro)⁸²⁾, APOE1 (156_173del)⁸³⁾, and APOE Osaka/Kurashiki (Arg158Pro)^84, ⁸⁵⁾. APOE Tsukuba (Arg114Cys) was identified as a mutation near Cys112 in helix 3 ⁸⁶⁾. No dyslipidemia was seen in these cases, but proteinuria led to renal biopsy, which showed glomerular capillary lumen dilatation and apoE deposition containing pale-stained clots with a layered structure. Another variant, APOE Kyoto (Arg25Cys), is located upstream of helix 1 of the N-terminal domain (Fig.5, Table 3)⁸⁷⁾. A survey of LPG-affected families also revealed that each variant exhibits low penetrance. APOE Kyoto was also reported as a compound heterozygote of p.Arg50His (Arg32His)⁸⁸⁾ and APOE Hong Kong (Asp230Tyr)⁸⁹⁾, while APOE Chicago was also reported as a compound heterozygote of APOE5 (Glu3Lys)⁹⁰⁾. It is likely that APOE Kyoto and APOE Chicago act in the pathogenesis of LPG, although this has not been investigated in detail.

As for incorrectly reported variants, APOE Ganzhou (Arg43Cys)⁹¹⁾ is correctly described as APOE (p.Arg43Cys), which is the same variant as APOE Kyoto (Arg25Cys)⁸⁷⁾. Meanwhile, APOE (p.Arg150Cys)⁹²⁾ is correctly identified as APOE (Arg150Cys), the same variant as APOE Modena (Arg150Cys)⁷⁸⁾.

The majority of LPG cases have been reported in Japan and China. APOE Sendai (Arg145Pro) was observed mainly in central and northern Japan, especially in Yamagata and Miyagi, but not in China^{71, 93)}. Moreover, APOE Kyoto (Arg25Cys)⁸⁷⁾ has been reported as the most common variant in LPG worldwide, including southwestern China, Japan, France, and the United States^{70, 94)}. Because the Chinese have been more involved in international population movements in ancient times than the Japanese, the APOE Kyoto gene could have spread from China to other countries around the world⁷¹⁾. Meanwhile, APOE Tokyo/Maebashi (141–143del) has been reported in cases from Japan and eastern China⁹⁴⁾. In animal models, APOE Sendai (Arg145Pro) and APOE Kyoto (Arg25Cys) variants have been expressed in APOE-deficient mice, with LPG-like renal pathology having been observed in each^{95, 96)}.

ApoE2 Homozygote Glomerulopathy and APOE Toyonaka (Ser197Cys)

ApoE2 (Arg158Cys) homozygote glomerulopathy has been reported in 10 cases worldwide^{97, 98)}. The histological features of renal biopsies of ApoE2 homozygote glomerulopathy include a prominent foamy macrophage infiltrate that can be explained by the mechanism of atherosclerosis glomerulosclerosis⁹⁹⁾. In some cases of apoE2 homozygote glomerulopathy, non-lamellar lipoprotein thrombi were observed, which is distinct from lipoprotein glomerulopathy¹⁰⁰⁾. In the presence of diabetes, it is often difficult to distinguish between ApoE2 homozygote glomerulopathy and diabetic nephropathy without a diagnosis of type III HLP.

A new glomerular disease was identified in four non-consanguineous carriers possessing the novel variant APOE Toyonaka (Ser197Cys) (Fig.5, Table 3)^{99, 101-103)}. This variant was considered to be in linkage disequilibrium with apoE2 (Arg158Cys). It was reported that glomerular lesions only occurred in APOE Toyonaka (Ser197Cys, Arg158Cys) when the other allele was ApoE2. The first and fourth reported cases presented with proteinuria and hematuria, but not dyslipidemia, and renal biopsy revealed nonimmune membranous nephropathy-like features in the glomeruli^{101, 98)}. Tandem mass spectrometry of the glomeruli identified an accumulation of apoE, and high serum apoE levels were seen. The other two cases were accompanied by marked hyperlipidemia and histologically showed foam cells and non-lamellar lipoprotein thrombi frequently observed in apoE2 homozygote glomerulopathy^{99, 102)}.

APOE Variants Associated with other Lipid Abnormalities

Hypercholesterolemia (HCh) and hypertriglycemia (HTG) are conditions that can occur even in the absence of APOE variants. The APOE variants described below have been reported from cases of hyperlipidemia (Table 4), although some cases may have been caused by factors other than APOE variants. Note that HCh and HTG in the same cases or in the same families are defined as CHL in Table 4.

Table 4. Variants associated with other lipid abnormalities.

No.	Variant	Protein sequence change	Genomic change^＊	rs number	Structure	ApoE phenotypes	Characteristics	gnomAD/ TOPMed^＃ frequency	Ref.
1	APOE p.Thr11Ala	p.Thr11Ala	c.31A>G	rs144354013	Signal	NA	CHL	0.00017^＃	40
2	APOE5 (Glu3Lys)	p.Glu21Lys	c.61G>A	rs121918392	N-ter	E5	CHL	0.000007	104,14,107
3	APOE4 Freiburg/ Pittsburgh (Leu28Pro, Cys112Arg)	p.Leu46Pro, p.Cys130Arg	c.137T>C	rs769452	Helix 1	E4	CHL, AD	0.00252	108,109
4	APOE p.Met82Ile (Met64Ile)	p.Met82Ile	c.246G>T	rs557845700	Helix 2	NA	HTG	0.000014	44
5	APOE5 Frankfurt (Gln81Lys, Cys112Arg)	p.Gln99Lys, p.Cys130Arg	c.295C>A	rs1180612218	Helix 2_3	E5	CHL	0.000004	112
6	APOE5 (Pro84Arg, Cys112Arg)	p.Pro102Arg, p.Cys130Arg	c.305C>G	rs11083750	Helix 2_3	E5	HCh	0.0000284	113
7	APOE p.Pro102Leu (Pro84Leu)	p.Pro102Leu	c.305C>T	rs11083750	Helix 2_3	E3	FH	0.000028	40
8	APOE Arg114Pro	p.Arg132Pro	c.395G>C	rs1263042140	Helix 3	E2	HCh	0.000004^＃	43
9	APOE p.Arg137Cys (Arg119Cys)	p.Arg137Cys	c.409C>T	rs573658040	Helix 3	NA	FH	0.000006	40
10	APOE p.Arg137His (Arg119His)	p.Arg137His	c.410G>A	rs11542035	Helix 3	NA	FH	0.000019	40
11	APOE5 (Val135_ Arg142dup)	p.Val153_ Arg160dup	c.457_480dup24	NA	Helix 4	E5	HTG	NA	114
12	APOE p.Leu155Phe (Leu137Phe)	p.Leu155Phe	c.463 C>T	rs1018669382	Helix 4	NA	FH	0.000007	40
13	APOE p.Leu167del (Leu149del)	p.Leu167del	c.499_501delCTC, c.500_502delTCC	rs515726148	Helix 4	E3	FH	0.00002	115,116,117
14	APOE p.Val179Ala (Val161Ala)	p.Val179Ala	c.536T>C	rs1421977676	Helix 4	NA	CHL	0.000008	40
15	APOE p.Gly191Cys (Gly173Cys)	p.Gly191Cys	c.571G>T	rs1265472491	Hinge	NA	HCh	0.000007	44
16	APOE1 Baden (Arg180Cys, Arg158Cys)	p.Arg198Cys, p.Arg176Cys	c.592C>T	rs1426426514	Hinge	E1	HTG	0.000011	119
17	APOE p.Val213Glu (Val195Glu)	p.Val213Glu	c.638T>A	rs1227709957	Hinge	NA	FH	0.00005	40
18	APOE p.Gly218Cys (Gly200Cys)	p.Gly218Cys	c.652G>T	rs1488379910	Hinge	NA	FH	0.00007^＃	40
19	APOE p.Pro220Leu (Pro202Leu)	p.Pro220Leu	c.659C>T	rs1265743589	Hinge	NA	CHL	0.000008	44
20	APOE p.Arg235Trp (Arg217Trp)	p.Arg235Trp	c.703C>T	rs530010303	C-ter	NA	FH	0.000023	29
21	APOE2 Fukuoka (Arg224Gln)	p.Arg242Gln	c.725G>A	rs267606663	C-ter	E2	FH	0.000004^＃	120
22	APOE2 Dunedin (Arg228Cys)	p.Arg246Cys	c.736C>T	rs121918395	C-ter	E2	HTG	0.000057	121
23	APOE p.Glu249Lys (Glu231Lys)	p.Glu249Lys	c.745G>A	rs762906934	C-ter	NA	CHL	NA	40
24	APOE p.Glu252Lys (Glu234Lys)	p.Glu252Lys	c.754G>A	NA	C-ter	NA	CHL	NA	40
25	APOE2 (Val236Glu)	p.Val254Glu	c.761T>A	rs199768005	C-ter	E2	CHL	0.000452	122
26	APOE7 Suita (Glu244Lys, Glu245Lys)	p.Glu262Lys, p.Glu263Lys	c.784G>A, c.787G>A	rs140808909, rs190853081	C-ter	E7	CHL	0.000199	123,14
27	APOE3 (Arg251Gly, Cys112Arg)	p.Arg269Gly, p.Cys130Arg	c.805C>G	rs267606661	C-ter	E3	CHL	0.00036	122
28	APOE1 (Leu252Glu, Arg158Cys)	p.Leu270Glu, p.Arg176Cys	c.808C>G, c.809T>A	rs992440908, NA	C-ter	E1	HCh	NA	122

Open in a new tab

^＊: Main mutation sites are shown, gnomAD: Genome Aggregation Database, TOPMed: Trans-Omics for Precision Medicine, ^＃: TOPMed frequency, Ref.: references, NA: not available, Signal: signal peptide, N-ter: N-terminal domain, C-ter: C-terminal domain, Hinge: hinge domain, FH: familial hypercholesterolemia including autosomal dominant hypercholesterolemia (ADH) and severe familial type III HLP, HCh: hypercholesterolemia, HTG: hypertriglyceridemia, CHL: combined hyperlipidemia, AD: Alzheimer’s disease

APOE5 (Glu3Lys) is predominantly present in the Japanese population^{14, 104)} and has been shown to be associated with increased binding to the LDL receptor compared with apoE3 ¹⁰⁵⁾. Carriers of APOE5 (Glu3Lys), including a homozygote, have been shown to exhibit high lipoprotein levels without type III HLP^{106, 107)}.

APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) was found in the same year in a screening focused on hyperlipidemia and in a screening for AD^{108, 109)}. Four APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) homozygotes were reported to have various types of hyperlipoproteinemia (types IIa, IIb, IV, V), including two hypertriglyceridemic patients with coronary artery disease¹⁰⁸⁾. APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) heterozygotes tended to have higher triglyceride levels. The APOE4 isoform has consistently emerged as a factor conferring susceptibility to late-onset AD. Studies have reported that APOE4 Freiburg/Pittsburgh (Leu28Pro, Cys112Arg) was structurally unstable and was associated with a higher risk of developing AD than APOE4 (Cys112Arg)^{110, 111)}. In addition, a case of an APOE p.Met82Ile (Met64Ile) heterozygote showed hypertriglyceridemia⁴⁴⁾. Moreover, APOE5 Frankfurt (Gln81Lys, Cys112Arg) heterozygosity was identified in a 43-year-old man with moderate CHL¹¹²⁾. Furthermore, APOE5 (Pro84Arg,Cys112Arg) heterozygosity was found in a 54-year-old woman of European descent with elevated LDL cholesterol levels¹¹³⁾. A case of an APOE (Arg114Pro) heterozygote was also found upon the screening of diabetic patients in the UK who presented with hypercholesterolemia, but this patient’s serum lipid levels were normalized by 10 mg of simvastatin⁴³⁾. Finally, APOE5 (Val135_Arg142dup ValArgLeuAlaSerHisLeuArg) heterozygosity was detected in a patient with elevated triglyceride levels¹¹⁴⁾.

As another example of an APOE variant, APOE p.Leu167del (Leu149del) was originally reported to be associated with sea blue histiocytosis and familial combined hyperlipidemia^115-117). Subsequently, whole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH^{29, 57, 118)}. This variant was also erroneously reported as APOE p.Leu149del^{116, 117)}.

APOE p.Gly191Cys (Gly173Cys), APOE1 Barden (Arg180Cys), and APOE p.Pro220Leu (Pro202Leu) were shown to be located in the hinge region^{44, 119)}. Moreover, a case exhibiting APOE p.Gly191Cys (Gly173Cys) heterozygosity showed isolated hypercholesterolemia⁴⁴⁾. Furthermore, two APOE1 Barden (Arg180Cys) heterozygotes in a family study showed hypertriglyceridemia¹¹²⁾, while a case of APOE p.Pro220Leu (Pro202Leu) with CHL was also reported⁴⁴⁾.

The C-terminal domain of APOE has high affinity for lipids, and there are several amphipathic α-helices in this domain that are responsible for the binding of apoE to lipids. Within a Norwegian hyperlipidemic cohort, APOE p.Arg235Trp (Arg217Trp) was found in a 56-year-old man with total cholesterol, triglyceride, LDL, and HDL levels of 363, 239, 247, and 69.6 mg/dL, respectively, along with the apoE3/E4 isoforms²⁹⁾.

Elsewhere, APOE2 Fukuoka (Arg224Gln) heterozygosity was identified in a 54-year-old Japanese woman with xanthomas¹²⁰⁾. When untreated (at 48 years old), she had dyslipidemia with total cholesterol of 1149 mg/dL and triglycerides of 1162 mg/dL. Possibly because of the variant being located in the C-terminal domain, recombinant APOE2 Fukuoka (Arg224Gln) showed almost the same LDL receptor-binding activity and heparin-binding capacity as recombinant APOE3 ¹²⁰⁾. APOE2 Dunedin (Arg228Cys)¹²¹⁾, APOE2 (Val236Glu)¹²²⁾, APOE7 Suita (Glu244,245Lys)^{123, 14)} (all heterozygotes), and APOE3 (Arg251 Gly, Cys112Arg) ¹²²⁾ in the C-terminal domain were identified as variants that cause hypertriglyceridemia or CHL. APOE1 (Leu252Glu, Arg158Cys) was found in the course of an apoE screening among hypercholesterolemic patients in Münster in 1985¹²²⁾.

Finally, 10 novel APOE variants, namely, APOE p.Thr11Ala, APOE p.Pro102Leu (Pro84Leu), APOE p.Arg137Cys (Arg119Cys), APOE p.Arg137His (Arg119His), APOE p.Leu155Phe (Leu137Phe), APOE p.Val179Ala (Val161Ala), APOE p.Val213Glu (Val195Glu), APOE p.Gly218Cys (Gly200Cys), APOE p.Glu249Lys (Glu231Lys), and APOE p.Glu252Lys (Glu234Lys), were reported in a recent French cohort of ADH and CHL patients (Table 4)⁴⁰⁾.

Other Reported APOE Variants

This section addresses APOE variants without lipid abnormalities and APOE variants without any stated abnormalities of lipid metabolism. APOE p.Arg108Trip (Arg90Trp) and APOE p.Tyr136His (Tyr118His) heterozygotes were detected in a normolipidemic group (Table 5)⁴⁴⁾. Moreover, screening of diabetic patients in the United Kingdom found one African patient who was heterozygous for APOE (Arg150His) with the E2/E2 phenotype, but no serum lipid abnormalities⁴³⁾. Elsewhere, APOE5 (Glu212Lys) was identified in a Turkish family¹²⁴⁾. Examination of the proband’s kindred revealed six heterozygous and two homozygous variant carriers. Compared with the non-carriers, carriers of the variant had slightly higher triglyceride levels (110.7 versus 98.3 mg/L). In another study, APOE5 (Gln204Lys, Cys112Arg) and APOE5 (Glu212Lys) were found to be present at almost polymorphic levels (allele frequencies: 0.006 and 0.012–0.013, respectively) in the Ethiopian population and no subjects with these variants had abnormal lipid or apolipoprotein patterns¹²⁵⁾. Moreover, APOE4’ (Arg274His, Cys112Arg) and APOE4 (Ser296Arg) were identified from cases selected during IEF-phenotype screening of a randomly collected population of healthy 35-year-old Dutch males, and they were normolipidemic¹²²⁾.

Table 5. Other reported APOE variants .

No.	Variant	Protein sequence change	Genomic change^＊	rs number	Protein structure	Characteristics	Ref.
1	APOE p.Thr11Ser	p.Thr11Ser	c.31A>T	rs144354013	Signal	NA	127
2	APOE p.Phe12Tyr	p.Phe12Tyr	c.35T>A	rs747078681	Signal	NA	127
3	APOE p.Ala23Val (Ala5Val)	p.Ala23Val	c.68C>T	rs776242156	N-ter	NA	127
4	APOE p.Arg33Cys (Arg15Cys)	p.Arg33Cys	c.97C>T	rs752079771	N-ter	NA	127
5	APOE p.Arg50Cys (Arg32Cys)	p.Arg50Cys	c.148C>T	rs11542029	Helix 1	NA	126
6	APOE p.Thr60Ala (Thr42Ala)	p.Thr60Ala	c.178A>G	rs28931576	Helix 1	NA	126
7	APOE p.Ser72Phe (Ser54Phe)	p.Ser72Phe	c.215C>T	rs1969840702	Helix 2	NA	127
8	APOE p.Pro102Gln (Pro84Gln)	p.Pro102Gln	c.305C>A	rs11083750	Helix 2-3	NA	126
9	APOE p.Arg108Trip (Arg90Trp)	p.Arg108Trp	c.322C>T	rs1050106163	Helix 3	NL	44
10	APOE p.Glu114Lys (Glu96Lys)	p.Glu114Lys	c.340G>A	rs1169728519	Helix 3	NA	127
11	APOE p.Ala117Thr (Ala99Thr)	p.Ala117Thr	c.349G>A	rs28931577	Helix 3	NA	126
12	APOE p.Arg132Ser (Arg114Ser)	p.Arg132Ser	c.394C>A	rs11542041	Helix 3	NA	126
13	APOE p.Tyr136His (Tyr118His)	p.Tyr136His	c.406T>C	rs1969862344	Helix 3	NL	44
14	APOE p.Glu139Val (Glu121Val)	p.Glu139Val	c.416A>T	rs41382345	Helix 3	NA	126
15	APOE p.Glu150Gly (Glu132Gly)	p.Glu150Gly	c.449A>G	rs11542034	Helix 4	NA	126
16	APOE p.Arg152Gln (Arg134Gln)	p.Arg152Gln	c.455G>A	rs28931578	Helix 4	NA	126
17	APOE p.Lys161Asn (Lys143Asn)	p.Lys161Asn	c.483G>T	rs867215645	Helix 4	NA	127
18	APOE (Arg150His)	p.Arg168His	c.503G>A	rs376170967	Helix 4	NL	43
19	APOE p.Glu189Lys (Glu171Lys)	p.Glu189Lys	c.565G>A	rs11542032	Hinge	NA	126
20	APOE p.Gln205Arg (Gln187Arg)	p.Gln205Arg	c.614A>G	rs11542030	Hinge	NA	126
21	APOE p.Ala210Ser (Ala192Ser)	p.Ala210Ser	c.628G>T	NA	Hinge	NA	127
22	APOE p.Ser215Phe (Ser197Phe)	p.Ser215Phe	c.644C>T	rs11542027	Hinge	NA	127
23	APOE p.Gly218Ser (Gly200Ser)	p.Gly218Ser	c.652G>A	rs1488379910	Hinge	NA	127
24	APOE5 (Gln204Lys, Cys112Arg)	p.Gln222Lys, p.Cys130Arg	c.664C>A	rs1181840153	C-ter	NL	125
25	APOE5 (Glu212Lys)	p.Glu230Lys	c.688G>A	rs567353589	C-ter	NL	124,125
26	APOE4’ (Arg274His, Cys112Arg)	p.Arg292His, p.Cys130Arg	c.875G>A	rs121918398	C-ter	NL	122
27	APOE p.Val305Met (Val287Met)	p.Val305Met	c.913G>A	rs749102800	C-ter	NA	127
28	APOE4 (Ser296Arg)	p.Ser314Arg	c.940A>C	rs28931579	C-ter	NL	122

Open in a new tab

^＊: Main mutation sites are shown, Ref.: references, Signal: signal peptide, N-ter: N-terminal domain, Hinge: hinge domain, C-ter: C-terminal domain, NA: not available, NL: no lipid abnormalities

The following 10 variants, APOE p.Arg50Cys (Arg32Cys), APOE p.Thr60Ala (Thr42Ala), APOE p.Pro102Gln (Pro84Gln), APOE p.Ala117Thr (Ala99Thr), APOE p.Arg132Ser (Arg114Ser), APOE p.Glu139Val (Glu121Val), APOE p.Glu150Gly (Glu132Gly), APOE p.Arg152Gln (Arg134Gln), APOE p.Glu189Lys (Glu171Lys), and APOE p.Gln205Arg (Gln187Arg), have only been analyzed in silico for APOE SNPs and their clinical data were unknown (Table 5)¹²⁶⁾. Genetic screening of the APOE gene for an association with dementia conducted in Denmark reported 20 rare nonsynonymous APOE variants in 105,597 individuals¹²⁷⁾. Nine of these variants had already been reported, but the following 11 variants had not (Table 5): APOE p.Thr11Ser, APOE p.Phe12Tyr, APOE p.Ala23Val (Ala5Val), APOE p.Arg33Cys (Arg15Cys), APOE p.Ser72Phe (Ser54Phe), APOE p.Glu114Lys (Glu96Lys), APOE p.Lys161Asn (Lys143Asn), APOE p.Ala210Ser (Ala192Ser), APOE p.Ser215Phe (Ser197Phe), APOE p.Gly218Ser (Gly200Ser), and APOE p.Val305Met (Val287Met) ¹²⁷⁾.

Conclusion

In this review, the importance of apoE in lipoprotein metabolism was demonstrated and the relationship between APOE variants and the pathology was explained as clearly as possible based on our current understanding. Abnormalities caused by APOE variants were classified and APOE variants were also described to the extent possible in order of domain and amino acid number (Supplemental Table 1). However, the present review also has some limitations. Here, we have reviewed the variants in and around the exons of the APOE gene that affect apoE as a protein, as reported in the literature to date. As such, the APOE variants in this review do not include synonymous substitutions, mutations in regulatory regions, intronic mutations other than in splicing sites, or linkage disequilibrium with other gene regions. We also did not review the very large number of papers analyzing the relationship between Alzheimer’s disease and APOE variants. Nonetheless, we consider this work to be valuable given that ApoE is not only a very important apoprotein, but also has genetic variants that readily cause pathological conditions.

Conflict of Interest

The authors have no conflicts of interest to declare.

References

1).Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR and Blum C: Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res, 1982; 23: 911-914 [PubMed] [Google Scholar]
2).Zhang SH, Reddick RL, Piedrahita JA and Maeda N: Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science, 1992; 258: 468-471 [DOI] [PubMed] [Google Scholar]
3).Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM and Breslow JL: Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell, 1992; 71: 343-353 [DOI] [PubMed] [Google Scholar]
4).Mahley RW, Weisgraber KH and Huang Y: Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res, 2009; 50 Suppl: S183-188 [DOI] [PMC free article] [PubMed] [Google Scholar]
5).Mahley RW: Apolipoprotein E: Remarkable Protein Sheds Light on Cardiovascular and Neurological Diseases. Clin Chem, 2017; 63: 14-20 [DOI] [PubMed] [Google Scholar]
6).Martinez-Martinez AB, Torres-Perez E, Devanney N, Del Moral R, Johnson LA and Arbones-Mainar JM: Beyond the CNS: The many peripheral roles of APOE. Neurobiol Dis, 2020; 138: 104809 [DOI] [PMC free article] [PubMed] [Google Scholar]
7).Marais AD: Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology, 2019; 51: 165-176 [DOI] [PubMed] [Google Scholar]
8).Mahley RW and Rall SC, Jr.: Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet, 2000; 1: 507-537 [DOI] [PubMed] [Google Scholar]
9).Wilson C, Wardell MR, Weisgraber KH, Mahley RW and Agard DA: Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science, 1991; 252: 1817-1822 [DOI] [PubMed] [Google Scholar]
10).Dolai S, Cherakara S and Garai K: Apolipoprotein E4 exhibits intermediates with domain interaction. Biochim Biophys Acta Proteins Proteom, 2020; 1868: 140535 [DOI] [PubMed] [Google Scholar]
11).Chen J, Li Q and Wang J: Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A, 2011; 108: 14813-14818 [DOI] [PMC free article] [PubMed] [Google Scholar]
12).Weisgraber KH, Rall SC, Jr., Mahley RW, Milne RW, Marcel YL and Sparrow JT: Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J Biol Chem, 1986; 261: 2068-2076 [PubMed] [Google Scholar]
13).Hixson JE and Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res, 1990; 31: 545-548 [PubMed] [Google Scholar]
14).Matsunaga A, Sasaki J, Moriyama K, Arakawa F, Takada Y, Nishi K, Hidaka K and Arakawa K: Population frequency of apolipoprotein E5 (Glu3-->Lys) and E7 (Glu244-->Lys, Glu245-->Lys) variants in western Japan. Clin Genet, 1995; 48: 93-99 [PubMed] [Google Scholar]
15).Belloy ME, Napolioni V and Greicius MD: A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward. Neuron, 2019; 101: 820-838 [DOI] [PMC free article] [PubMed] [Google Scholar]
16).Weisgraber KH, Innerarity TL and Mahley RW: Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem, 1982; 257: 2518-2521 [PubMed] [Google Scholar]
17).Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW and Agard DA: Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure, 1994; 2: 713-718 [DOI] [PubMed] [Google Scholar]
18).Aslam MM, Fan KH, Lawrence E, Bedison MA, Snitz BE, DeKosky ST, Lopez OL, Feingold E and Kamboh MI: Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk. Mol Psychiatry, 2023; 28: 4451-4462 [DOI] [PMC free article] [PubMed] [Google Scholar]
19).Phillips MC: Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life, 2014; 66: 616-623 [DOI] [PubMed] [Google Scholar]
20).Rensen PC and van Berkel TJ: Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem, 1996; 271: 14791-14799 [DOI] [PubMed] [Google Scholar]
21).Huang Y, Liu XQ, Rall SC, Jr., Taylor JM, von Eckardstein A, Assmann G and Mahley RW: Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem, 1998; 273: 26388-26393 [DOI] [PubMed] [Google Scholar]
22).Paik YK, Chang DJ, Reardon CA, Davies GE, Mahley RW and Taylor JM: Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci U S A, 1985; 82: 3445-3449 [DOI] [PMC free article] [PubMed] [Google Scholar]
23).Mahley RW, Huang Y and Rall SC, Jr.: Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res, 1999; 40: 1933-1949 [PubMed] [Google Scholar]
24).Hopkins PN, Brinton EA and Nanjee MN: Hyperlipoproteinemia type 3: the forgotten phenotype. Curr Atheroscler Rep, 2014; 16: 440 [DOI] [PubMed] [Google Scholar]
25).Blum CB: Type III Hyperlipoproteinemia: Still Worth Considering? Prog Cardiovasc Dis, 2016; 59: 119-124 [DOI] [PubMed] [Google Scholar]
26).Civeira F, Pocovi M, Cenarro A, Casao E, Vilella E, Joven J, Gonzalez J, Garcia-Otin AL and Ordovas JM: Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis, 1996; 127: 273-282 [DOI] [PubMed] [Google Scholar]
27).Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H and Marz W: Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat, 1998; 11: 417-423 [DOI] [PubMed] [Google Scholar]
28).Sniderman AD: Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipoproteinemia. Clin Chem, 2019; 65: 225-227 [DOI] [PubMed] [Google Scholar]
29).Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchke P, Jais JP, French Research Network on ADH, Abifadel M, Kathiresan S, Leren TP, Rabes JP, Boileau C and Varret M: Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat, 2013; 34: 83-87 [DOI] [PMC free article] [PubMed] [Google Scholar]
30).Mabuchi H, Itoh H, Takeda M, Kajinami K, Wakasugi T, Koizumi J, Takeda R and Asagami C: A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism, 1989; 38: 115-119 [DOI] [PubMed] [Google Scholar]
31).Kurosaka D, Teramoto T, Matsushima T, Yokoyama T, Yamada A, Aikawa T, Miyamoto Y and Kurokawa K: Apolipoprotein E deficiency with a depressed mRNA of normal size. Atherosclerosis, 1991; 88: 15-20 [DOI] [PubMed] [Google Scholar]
32).Schaefer EJ, Gregg RE, Ghiselli G, Forte TM, Ordovas JM, Zech LA and Brewer HB, Jr.: Familial apolipoprotein E deficiency. J Clin Invest, 1986; 78: 1206-1219 [DOI] [PMC free article] [PubMed] [Google Scholar]
33).Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G and Zannis VI: The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene. J Biol Chem, 1987; 262: 2310-2315 [PubMed] [Google Scholar]
34).Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Duncan JL, Miller BL, Kane JP, Kwok PY and Malloy MJ: Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol, 2014; 71: 1228-1236 [DOI] [PMC free article] [PubMed] [Google Scholar]
35).Feussner G, Dobmeyer J, Grone HJ, Lohmer S and Wohlfeil S: A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet, 1996; 58: 281-291 [PMC free article] [PubMed] [Google Scholar]
36).Lohse P, Brewer HB, 3rd, Meng MS, Skarlatos SI, LaRosa JC and Brewer HB, Jr.: Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res, 1992; 33: 1583-1590 [PubMed] [Google Scholar]
37).Feussner G, Funke H, Weng W, Assmann G, Lackner KJ and Ziegler R: Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/’null’ genotype. Eur J Clin Invest, 1992; 22: 599-608 [DOI] [PubMed] [Google Scholar]
38).Feussner G and Ziegler R: Response to therapy of a type III hyperlipoproteinemic subject with the rare apolipoprotein E1 (Gly127----Asp, Arg158----Cys) variant. Clin Investig, 1992; 70: 614-617 [DOI] [PubMed] [Google Scholar]
39).Leren TP, Strom TB and Berge KE: Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene. Mol Genet Metab Rep, 2016; 9: 67-70 [DOI] [PMC free article] [PubMed] [Google Scholar]
40).Abou Khalil Y, Marmontel O, Ferrieres J, Paillard F, Yelnik C, Carreau V, Charriere S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrie A, Rabes JP and Varret M: APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci, 2022; 23: [DOI] [PMC free article] [PubMed] [Google Scholar]
41).Dijck-Brouwer DA, van Doormaal JJ, Kema IP, Brugman AM, Kingma AW and Muskiet FA: Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem, 2005; 42: 264-268 [DOI] [PubMed] [Google Scholar]
42).Tate JR, Hoffmann MM, Lovelock PK, Kesting JB and Shaw JT: Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian. Ann Clin Biochem, 2001; 38: 46-53 [DOI] [PubMed] [Google Scholar]
43).Stephens JW, Sozen MM, Whittall RA, Caslake MJ, Bedford D, Acharya J, Hurel SJ and Humphries SE: Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem, 2005; 51: 119-124 [DOI] [PubMed] [Google Scholar]
44).Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 [DOI] [PubMed] [Google Scholar]
45).Smit M, de Knijff P, van der Kooij-Meijs E, Groenendijk C, van den Maagdenberg AM, Gevers Leuven JA, Stalenhoef AF, Stuyt PM, Frants RR and Havekes LM: Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146----gln) variant results in a dominant mode of inheritance. J Lipid Res, 1990; 31: 45-53 [PubMed] [Google Scholar]
46).Khalil YA, Rabes JP, Boileau C and Varret M: APOE gene variants in primary dyslipidemia. Atherosclerosis, 2021; 328: 11-22 [DOI] [PubMed] [Google Scholar]
47).Feussner G, Albanese M, Mann WA, Valencia A and Schuster H: Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia. Eur J Clin Invest, 1996; 26: 13-23 [DOI] [PubMed] [Google Scholar]
48).Wardell MR, Brennan SO, Janus ED, Fraser R and Carrell RW: Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J Clin Invest, 1987; 80: 483-490 [DOI] [PMC free article] [PubMed] [Google Scholar]
49).Horie Y, Fazio S, Westerlund JR, Weisgraber KH and Rall SC, Jr.: The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J Biol Chem, 1992; 267: 1962-1968 [PubMed] [Google Scholar]
50).Havel RJ, Kotite L, Kane JP, Tun P and Bersot T: Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest, 1983; 72: 379-387 [DOI] [PMC free article] [PubMed] [Google Scholar]
51).Richard P, de Zulueta MP, Beucler I, De Gennes JL, Cassaigne A and Iron A: Identification of a new apolipoprotein E variant (E2 Arg142-->Leu) in type III hyperlipidemia. Atherosclerosis, 1995; 112: 19-28 [DOI] [PubMed] [Google Scholar]
52).Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, Kaneko S and Arakawa K: Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia. Biochim Biophys Acta, 1992; 1128: 58-64 [DOI] [PubMed] [Google Scholar]
53).Mann WA, Lohse P, Gregg RE, Ronan R, Hoeg JM, Zech LA and Brewer HB, Jr.: Dominant expression of type III hyperlipoproteinemia. Pathophysiological insights derived from the structural and kinetic characteristics of ApoE-1 (Lys146-->Glu). J Clin Invest, 1995; 96: 1100-1107 [DOI] [PMC free article] [PubMed] [Google Scholar]
54).Hoffer MJ, Niththyananthan S, Naoumova RP, Kibirige MS, Frants RR, Havekes LM and Thompson GR: Apolipoprotein E1-Hammersmith (Lys146-->Asn; Arg147-->Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia. Atherosclerosis, 1996; 124: 183-189 [DOI] [PubMed] [Google Scholar]
55).van den Maagdenberg AM, de Knijff P, Stalenhoef AF, Gevers Leuven JA, Havekes LM and Frants RR: Apolipoprotein E*3-Leiden allele results from a partial gene duplication in exon 4. Biochem Biophys Res Commun, 1989; 165: 851-857 [DOI] [PubMed] [Google Scholar]
56).Weisgraber KH, Rall SC, Jr., Innerarity TL, Mahley RW, Kuusi T and Ehnholm C: A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1. J Clin Invest, 1984; 73: 1024-1033 [DOI] [PMC free article] [PubMed] [Google Scholar]
57).Wintjens R, Bozon D, Belabbas K, F MB, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M and Dufernez F: Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J Lipid Res, 2016; 57: 482-491 [DOI] [PMC free article] [PubMed] [Google Scholar]
58).Steinmetz A, Assefbarkhi N, Eltze C, Ehlenz K, Funke H, Pies A, Assmann G and Kaffarnik H: Normolipemic dysbetalipoproteinemia and hyperlipoproteinemia type III in subjects homozygous for a rare genetic apolipoprotein E variant (apoE1). J Lipid Res, 1990; 31: 1005-1013 [PubMed] [Google Scholar]
59).Minnich A, Weisgraber KH, Newhouse Y, Dong LM, Fortin LJ, Tremblay M and Davignon J: Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3’ (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res, 1995; 36: 57-66 [PubMed] [Google Scholar]
60).Sakuma N, Hibino T, Saeki T, Nagata T, Sato T, Okuda N, Matsunaga A and Sasaki J: Compound heterozygotes for a novel mutation, apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with severe type III hyperlipoproteinemia and familial hypercholesterolemia. J Atheroscler Thromb, 2014; 21: 983-988 [DOI] [PubMed] [Google Scholar]
61).Suehiro T, Yoshida K, Yamano T and Ohno F: Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi). Jpn J Med, 1990; 29: 587-594 [DOI] [PubMed] [Google Scholar]
62).Hidaka H, Tozuka M, Hidaka E, Yamauchi K, Ota H, Honda T and Katsuyama T: Characterization of an apolipoprotein E3 variant (Arg 145-->His) associated with mild hypertriglyceridemia. Ann Clin Lab Sci, 2001; 31: 163-170 [PubMed] [Google Scholar]
63).Lohse P, Mann WA, Stein EA and Brewer HB, Jr.: Apolipoprotein E-4Philadelphia (Glu13----Lys,Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem, 1991; 266: 10479-10484 [PubMed] [Google Scholar]
64).Abou Ziki MD, Strulovici-Barel Y, Hackett NR, Rodriguez-Flores JL, Mezey JG, Salit J, Radisch S, Hollmann C, Chouchane L, Malek J, Zirie MA, Jayyuosi A, Gotto AM, Jr. and Crystal RG: Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations. Am J Cardiol, 2014; 113: 302-308 [DOI] [PMC free article] [PubMed] [Google Scholar]
65).de Villiers WJ, van der Westhuyzen DR, Coetzee GA, Henderson HE and Marais AD: The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance. Arterioscler Thromb Vasc Biol, 1997; 17: 865-872 [DOI] [PubMed] [Google Scholar]
66).Okubo M, Aoyama Y, Harada K, Fukawa M, Tsukada T, Mokuno H, Yamada N and Murase T: A novel apolipoprotein E2 variant, E2Toranomon (Q187E), identified in a type III hyperlipoproteinemia patient with coronary atherosclerosis. Atherosclerosis, 1998; 140: 187-190 [DOI] [PubMed] [Google Scholar]
67).Hayakawa M, Okubo M, Katori H, Nagahama K, Murase T, Kobayashi T, Tanaka S, Nakanishi K, Odawara M, Matsushita H and Yamada A: A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy. Am J Kidney Dis, 2002; 39: E15 [DOI] [PubMed] [Google Scholar]
68).Saito T, Sato H, Kudo K, Oikawa S, Shibata T, Hara Y, Yoshinaga K and Sakaguchi H: Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis, 1989; 13: 148-153 [DOI] [PubMed] [Google Scholar]
69).Saito T, Matsunaga A and Oikawa S: Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis, 2006; 47: 199-211 [DOI] [PubMed] [Google Scholar]
70).Matsunaga A and Saito T: Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia. Clin Exp Nephrol, 2014; 18: 220-224 [DOI] [PubMed] [Google Scholar]
71).Saito T and Matsunaga A: Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis. Kidney Int, 2014; 85: 243-245 [DOI] [PubMed] [Google Scholar]
72).Oikawa S, Matsunaga A, Saito T, Sato H, Seki T, Hoshi K, Hayasaka K, Kotake H, Midorikawa H, Sekikawa A, Hara S, Abe K, Toyota T, Jingami H, Nakamura H and Sasaki J: Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 [DOI] [PubMed] [Google Scholar]
73).Konishi K, Saruta T, Kuramochi S, Oikawa S, Saito T, Han H, Matsunaga A and Sasaki J: Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron, 1999; 83: 214-218 [DOI] [PubMed] [Google Scholar]
74).Ogawa T, Maruyama K, Hattori H, Arai H, Kondoh I, Egashira T, Watanabe T, Kobayashi Y and Morikawa A: A new variant of apolipoprotein E (apo E Maebashi) in lipoprotein glomerulopathy. Pediatr Nephrol, 2000; 14: 149-151 [DOI] [PubMed] [Google Scholar]
75).Xie W, Xie Y, Lin Z, Xu X and 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; 14: 41 [DOI] [PMC free article] [PubMed] [Google Scholar]
76).Sam R, Wu H, Yue L, Mazzone T, Schwartz MM, Arruda JA, Dunea G and Singh AK: Lipoprotein glomerulopathy: a new apolipoprotein E mutation with enhanced glomerular binding. Am J Kidney Dis, 2006; 47: 539-548 [DOI] [PubMed] [Google Scholar]
77).Kinomura M, Sugiyama H, Saito T, Matsunaga A, Sada KE, Kanzaki M, Takazawa Y, Maeshima Y, Yanai H and Makino H: A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy. Nephrol Dial Transplant, 2008; 23: 751-756 [DOI] [PubMed] [Google Scholar]
78).Tsimihodimos V and Elisaf M: Lipoprotein glomerulopathy. Curr Opin Lipidol, 2011; 22: 262-269 [DOI] [PubMed] [Google Scholar]
79).Luo B, Huang F, Liu Q, Li X, Chen W, Zhou SF and Yu X: Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol, 2008; 28: 347-353 [DOI] [PMC free article] [PubMed] [Google Scholar]
80).Yokochi A, Matsunaga A, Kanemoto K, Tominaga N, Uda S and Saito T: Lipoprotein glomerulopathy with a novel apolipoprotein E variant, APOE Kanto (Asp 151dup). CEN Case Rep, 2024; [DOI] [PMC free article] [PubMed] [Google Scholar]
81).Bomback AS, Song H, D’Agati VD, Cohen SD, Neal A, Appel GB and Rovin BH: A new apolipoprotein E mutation, apoE Las Vegas, in a European-American with lipoprotein glomerulopathy. Nephrol Dial Transplant, 2010; 25: 3442-3446 [DOI] [PubMed] [Google Scholar]
82).Wu H, Yang Y and Hu Z: The Novel Apolipoprotein E Mutation ApoE Chengdu (c.518T>C, p.L173P) in a Chinese Patient with Lipoprotein Glomerulopathy. J Atheroscler Thromb, 2018; 25: 733-740 [DOI] [PMC free article] [PubMed] [Google Scholar]
83).Ando M, Sasaki J, Hua H, Matsunaga A, Uchida K, Jou K, Oikawa S, Saito T and Nihei H: A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int, 1999; 56: 1317-1323 [DOI] [PubMed] [Google Scholar]
84).Mitani A, Ishigami M, Watase K, Minakata T and Yamamura T: A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy. J Atheroscler Thromb, 2011; 18: 531-535 [DOI] [PubMed] [Google Scholar]
85).Tokura T, Itano S, Kobayashi S, Kuwabara A, Fujimoto S, Horike H, Satoh M, Komai N, Tomita N, Matsunaga A, Saito T, Sasaki T and Kashihara N: A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. J Atheroscler Thromb, 2011; 18: 536-541 [DOI] [PubMed] [Google Scholar]
86).Hagiwara M, Yamagata K, Matsunaga T, Arakawa Y, Usui J, Shimizu Y, Aita K, Nagata M, Koyama A, Zhang B, Mastunaga A, Saku K and Saito T: A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy. Nephrol Dial Transplant, 2008; 23: 381-384 [DOI] [PubMed] [Google Scholar]
87).Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, Tsuji E, Moriyama K, Koga T, Arakawa K, Oikawa S, Saito T, Kita T and Doi T: A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int, 1999; 56: 421-427 [DOI] [PubMed] [Google Scholar]
88).Li Y, Chen J, Zou Y, Wang W and Li G: Lipoprotein glomerulopathy resulting from compound heterogeneous mutations of APOE gene: A case report. Medicine (Baltimore), 2022; 101: e28718 [DOI] [PMC free article] [PubMed] [Google Scholar]
89).Cheung CY, Chan AO, Chan YH, Lee KC, Chan GP, Lau GT, Shek CC, Chau KF and Li CS: A rare cause of nephrotic syndrome: lipoprotein glomerulopathy. Hong Kong Med J, 2009; 15: 57-60 [PubMed] [Google Scholar]
90).Kodera H, Mizutani Y, Sugiyama S, Miyata T, Ehara T, Matsunaga A and Saito T: A Case of Lipoprotein Glomerulopathy with apoE Chicago and apoE (Glu3Lys) Treated with Fenofibrate. Case Rep Nephrol Dial, 2017; 7: 112-120 [DOI] [PMC free article] [PubMed] [Google Scholar]
91).Wang R, Zhao C, Chen W, Liu Z and Xie F: A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports. J Med Case Rep, 2022; 16: 78 [DOI] [PMC free article] [PubMed] [Google Scholar]
92).Ku M, Tao C, Zhou AA, Cheng Y and Wan QJ: A novel apolipoprotein E mutation (p.Arg150Cys) in a Chinese patient with lipoprotein glomerulopathy. Chin Med J (Engl), 2019; 132: 237-239 [DOI] [PMC free article] [PubMed] [Google Scholar]
93).Toyota K, Hashimoto T, Ogino D, Matsunaga A, Ito M, Masakane I, Degawa N, Sato H, Shirai S, Umetsu K, Tamiya G, Saito T and Hayasaka K: A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet, 2013; 58: 254-258 [DOI] [PubMed] [Google Scholar]
94).Li MS, Li Y, Liu Y, Zhou XJ and Zhang H: An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne), 2022; 9: 905007 [DOI] [PMC free article] [PubMed] [Google Scholar]
95).Ishigaki Y, Oikawa S, Suzuki T, Usui S, Magoori K, Kim DH, Suzuki H, Sasaki J, Sasano H, Okazaki M, Toyota T, Saito T and Yamamoto TT: Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice. J Biol Chem, 2000; 275: 31269-31273 [DOI] [PubMed] [Google Scholar]
96).Wu H, Yang J, Liu YQ, Lei S, Yang M, Yang Z, Yang Y and Hu Z: Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice. J Transl Med, 2021; 19: 97 [DOI] [PMC free article] [PubMed] [Google Scholar]
97).Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S and Muso E: Apolipoprotein E-related glomerular disorders. Kidney Int, 2020; 97: 279-288 [DOI] [PubMed] [Google Scholar]
98).Kawanishi K, Sawada A, Ochi A, Moriyama T, Mitobe M, Mochizuki T, Honda K, Oda H, Nishikawa T and Nitta K: Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature. Case Rep Nephrol Urol, 2013; 3: 128-135 [DOI] [PMC free article] [PubMed] [Google Scholar]
99).Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E and Saito T: A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep, 2019; 8: 106-111 [DOI] [PMC free article] [PubMed] [Google Scholar]
100).Sakatsume M, Kadomura M, Sakata I, Imai N, Kondo D, Osawa Y, Shimada H, Ueno M, Miida T, Nishi S, Arakawa M and Gejyo F: Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity. Kidney Int, 2001; 59: 1911-1918 [DOI] [PubMed] [Google Scholar]
101).Fukunaga M, Nagahama K, Aoki M, Shimizu A, Hara S, Matsunaga A, Muso E and Saito T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2. Case Rep Nephrol Dial, 2018; 8: 45-55 [DOI] [PMC free article] [PubMed] [Google Scholar]
102).Hirashima H, Komiya T, Toriu N, Hara S, Matsunaga A, Saito T and Muso E: A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka. Clin Nephrol Case Stud, 2018; 6: 45-51 [DOI] [PMC free article] [PubMed] [Google Scholar]
103).Koshino A, Takaeda C, Matsuno T, Kitajima S, Iwata Y, Sakai N, Nagahama K, Niida Y, Saito T, Yokoyama H and Wada T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits. Case Rep Nephrol Dial, 2022; 12: 96-104 [DOI] [PMC free article] [PubMed] [Google Scholar]
104).Yamanouchi Y, Arinami T, Tsuchiya S, Miyazaki R, Takaki H, Takano T and Hamaguchi H: Apolipoprotein E5 and E7 in apparently healthy Japanese males: frequencies and relation to plasma lipid levels. Jpn J Hum Genet, 1994; 39: 315-324 [DOI] [PubMed] [Google Scholar]
105).Dong LM, Yamamura T, Tajima S and Yamamoto A: Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3----Lys) and its binding to low density lipoprotein receptors. Biochem Biophys Res Commun, 1992; 187: 1180-1186 [DOI] [PubMed] [Google Scholar]
106).Tajima S, Yamamura T and Yamamoto A: Analysis of apolipoprotein E5 gene from a patient with hyperlipoproteinemia. J Biochem, 1988; 104: 48-52 [DOI] [PubMed] [Google Scholar]
107).Kobayashi J, Shirai K, Murano T, Misawa Y, Tashiro J, Yoshida T and Shinomiya M: A case of hyperlipidemia with homozygous apolipoprotein E5 (Glu3-->Lys). Biochim Biophys Acta, 2002; 1583: 117-121 [DOI] [PubMed] [Google Scholar]
108).Orth M, Weng W, Funke H, Steinmetz A, Assmann G, Nauck M, Dierkes J, Ambrosch A, Weisgraber KH, Mahley RW, Wieland H and Luley C: Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28-->Pro), on lipoproteins and the prevalence of coronary artery disease in whites. Arterioscler Thromb Vasc Biol, 1999; 19: 1306-1315 [DOI] [PubMed] [Google Scholar]
109).Kamboh MI, Aston CE, Perez-Tur J, Kokmen E, Ferrell RE, Hardy J and DeKosky ST: A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer’s disease. Neurosci Lett, 1999; 263: 129-132 [DOI] [PubMed] [Google Scholar]
110).Argyri L, Dafnis I, Theodossiou TA, Gantz D, Stratikos E and Chroni A: Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4. J Biol Chem, 2014; 289: 12931-12945 [DOI] [PMC free article] [PubMed] [Google Scholar]
111).Fan K, Francis L, Aslam MM, Bedison MA, Lawrence E, Acharya V, Snitz BE, Ganguli M, DeKosky ST, Lopez OL, Feingold E and Kamboh MI: Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease. Neurobiol Aging, 2023; 122: 107-111 [DOI] [PMC free article] [PubMed] [Google Scholar]
112).Ruzicka V, Marz W, Russ A, Fisher E, Mondorf W and Gross W: Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis. Electrophoresis, 1993; 14: 1032-1037 [DOI] [PubMed] [Google Scholar]
113).Wardell MR, Rall SC, Jr., Schaefer EJ, Kane JP and Weisgraber KH: Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity. J Lipid Res, 1991; 32: 521-528 [PubMed] [Google Scholar]
114).Yamanouchi Y, Takano T, Hamaguchi H and Tokunaga K: A novel apolipoprotein E5 variant with a 24-bp insertion causing hyperlipidemia. J Hum Genet, 2001; 46: 633-639 [DOI] [PubMed] [Google Scholar]
115).Nguyen TT, Kruckeberg KE, O’Brien JF, Ji ZS, Karnes PS, Crotty TB, Hay ID, Mahley RW and O’Brien T: Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]. J Clin Endocrinol Metab, 2000; 85: 4354-4358 [DOI] [PubMed] [Google Scholar]
116).Faivre L, Saugier-Veber P, Pais de Barros JP, Verges B, Couret B, Lorcerie B, Thauvin C, Charbonnier F, Huet F, Gambert P, Frebourg T and Duvillard L: Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation. Eur J Hum Genet, 2005; 13: 1186-1191 [DOI] [PubMed] [Google Scholar]
117).Solanas-Barca M, de Castro-Oros I, Mateo-Gallego R, Cofan M, Plana N, Puzo J, Burillo E, Martin-Fuentes P, Ros E, Masana L, Pocovi M, Civeira F and Cenarro A: Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. Atherosclerosis, 2012; 222: 449-455 [DOI] [PubMed] [Google Scholar]
118).Okorodudu DE, Crowley MJ, Sebastian S, Rowell JV and Guyton JR: Inherited lipemic splenomegaly and the spectrum of apolipoprotein E p.Leu167del mutation phenotypic variation. J Clin Lipidol, 2013; 7: 566-572 [DOI] [PubMed] [Google Scholar]
119).Hoffmann MM, Scharnagl H, Koster W, Winkler K, Wieland H and Marz W: Apolipoprotein E1 Baden (Arg(180)-->Cys). A new apolipoprotein E variant associated with hypertriglyceridemia. Clin Chim Acta, 2001; 303: 41-48 [DOI] [PubMed] [Google Scholar]
120).Moriyama K, Sasaki J, Takada Y, Arakawa F, Matsunaga A, Ito Y and Arakawa K: Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 --> Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta, 1996; 1301: 185-190 [DOI] [PubMed] [Google Scholar]
121).Wardell MR, Rall SC, Jr., Brennan SO, Nye ER, George PM, Janus ED and Weisgraber KH: Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity. J Lipid Res, 1990; 31: 535-543 [PubMed] [Google Scholar]
122).van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van’t Hooft FM, Assmann G, Hofker MH and et al.: Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet, 1993; 52: 937-946 [PMC free article] [PubMed] [Google Scholar]
123).Yanagi K, Yamashita S, Hiraoka H, Ishigami M, Kihara S, Hirano K, Sakai N, Nozaki S, Funahashi T, Kameda-Takemura K, Kubo M, Tokunaga K and Matsuzawa Y: Increased serum remnant lipoproteins in patients with apolipoprotein E7 (apo E Suita). Atherosclerosis, 1997; 131: 49-58 [DOI] [PubMed] [Google Scholar]
124).Feussner G, Scharnagl H, Scherbaum C, Acar J, Dobmeyer J, Lohrmann J, Wieland H and Marz W: Apolipoprotein E5 (Glu212-->Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res, 1996; 37: 1632-1645 [PubMed] [Google Scholar]
125).Scacchi R, De Stefano GF, Ruggeri M and Corbo RM: Genetic variation at apolipoprotein E locus in Ethiopia: An E5 variant corresponds to two different mutant alleles: E*5 (Glu212Lys) and E*5 (Gln204Lys; Cys112Arg). Human Biology, 2003; 75: 293-300 [DOI] [PubMed] [Google Scholar]
126).Masoodi TA, Al Shammari SA, Al-Muammar MN and Alhamdan AA: Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer’s Disease. Neurol Res Int, 2012; 2012: 480609 [DOI] [PMC free article] [PubMed] [Google Scholar]
127).Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG and Frikke-Schmidt R: APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement, 2020; 16: 1624-1637 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X28] 1).Zannis VI, Breslow JL, Utermann G, Mahley RW, Weisgraber KH, Havel RJ, Goldstein JL, Brown MS, Schonfeld G, Hazzard WR and Blum C: Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res, 1982; 23: 911-914 [PubMed] [Google Scholar]

[X29] 2).Zhang SH, Reddick RL, Piedrahita JA and Maeda N: Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science, 1992; 258: 468-471 [DOI] [PubMed] [Google Scholar]

[X30] 3).Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG, Rubin EM and Breslow JL: Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell, 1992; 71: 343-353 [DOI] [PubMed] [Google Scholar]

[X31] 4).Mahley RW, Weisgraber KH and Huang Y: Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res, 2009; 50 Suppl: S183-188 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X32] 5).Mahley RW: Apolipoprotein E: Remarkable Protein Sheds Light on Cardiovascular and Neurological Diseases. Clin Chem, 2017; 63: 14-20 [DOI] [PubMed] [Google Scholar]

[X33] 6).Martinez-Martinez AB, Torres-Perez E, Devanney N, Del Moral R, Johnson LA and Arbones-Mainar JM: Beyond the CNS: The many peripheral roles of APOE. Neurobiol Dis, 2020; 138: 104809 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X34] 7).Marais AD: Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology, 2019; 51: 165-176 [DOI] [PubMed] [Google Scholar]

[X35] 8).Mahley RW and Rall SC, Jr.: Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet, 2000; 1: 507-537 [DOI] [PubMed] [Google Scholar]

[X36] 9).Wilson C, Wardell MR, Weisgraber KH, Mahley RW and Agard DA: Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science, 1991; 252: 1817-1822 [DOI] [PubMed] [Google Scholar]

[X37] 10).Dolai S, Cherakara S and Garai K: Apolipoprotein E4 exhibits intermediates with domain interaction. Biochim Biophys Acta Proteins Proteom, 2020; 1868: 140535 [DOI] [PubMed] [Google Scholar]

[X38] 11).Chen J, Li Q and Wang J: Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A, 2011; 108: 14813-14818 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X39] 12).Weisgraber KH, Rall SC, Jr., Mahley RW, Milne RW, Marcel YL and Sparrow JT: Human apolipoprotein E. Determination of the heparin binding sites of apolipoprotein E3. J Biol Chem, 1986; 261: 2068-2076 [PubMed] [Google Scholar]

[X40] 13).Hixson JE and Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res, 1990; 31: 545-548 [PubMed] [Google Scholar]

[X41] 14).Matsunaga A, Sasaki J, Moriyama K, Arakawa F, Takada Y, Nishi K, Hidaka K and Arakawa K: Population frequency of apolipoprotein E5 (Glu3-->Lys) and E7 (Glu244-->Lys, Glu245-->Lys) variants in western Japan. Clin Genet, 1995; 48: 93-99 [PubMed] [Google Scholar]

[X42] 15).Belloy ME, Napolioni V and Greicius MD: A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward. Neuron, 2019; 101: 820-838 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X43] 16).Weisgraber KH, Innerarity TL and Mahley RW: Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem, 1982; 257: 2518-2521 [PubMed] [Google Scholar]

[X44] 17).Wilson C, Mau T, Weisgraber KH, Wardell MR, Mahley RW and Agard DA: Salt bridge relay triggers defective LDL receptor binding by a mutant apolipoprotein. Structure, 1994; 2: 713-718 [DOI] [PubMed] [Google Scholar]

[X45] 18).Aslam MM, Fan KH, Lawrence E, Bedison MA, Snitz BE, DeKosky ST, Lopez OL, Feingold E and Kamboh MI: Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk. Mol Psychiatry, 2023; 28: 4451-4462 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X46] 19).Phillips MC: Apolipoprotein E isoforms and lipoprotein metabolism. IUBMB Life, 2014; 66: 616-623 [DOI] [PubMed] [Google Scholar]

[X47] 20).Rensen PC and van Berkel TJ: Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicron-like triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem, 1996; 271: 14791-14799 [DOI] [PubMed] [Google Scholar]

[X48] 21).Huang Y, Liu XQ, Rall SC, Jr., Taylor JM, von Eckardstein A, Assmann G and Mahley RW: Overexpression and accumulation of apolipoprotein E as a cause of hypertriglyceridemia. J Biol Chem, 1998; 273: 26388-26393 [DOI] [PubMed] [Google Scholar]

[X49] 22).Paik YK, Chang DJ, Reardon CA, Davies GE, Mahley RW and Taylor JM: Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci U S A, 1985; 82: 3445-3449 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X50] 23).Mahley RW, Huang Y and Rall SC, Jr.: Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes. J Lipid Res, 1999; 40: 1933-1949 [PubMed] [Google Scholar]

[B24] 24).Hopkins PN, Brinton EA and Nanjee MN: Hyperlipoproteinemia type 3: the forgotten phenotype. Curr Atheroscler Rep, 2014; 16: 440 [DOI] [PubMed] [Google Scholar]

[X51] 25).Blum CB: Type III Hyperlipoproteinemia: Still Worth Considering? Prog Cardiovasc Dis, 2016; 59: 119-124 [DOI] [PubMed] [Google Scholar]

[X52] 26).Civeira F, Pocovi M, Cenarro A, Casao E, Vilella E, Joven J, Gonzalez J, Garcia-Otin AL and Ordovas JM: Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis, 1996; 127: 273-282 [DOI] [PubMed] [Google Scholar]

[X53] 27).Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H and Marz W: Molecular basis of type III hyperlipoproteinemia in Germany. Hum Mutat, 1998; 11: 417-423 [DOI] [PubMed] [Google Scholar]

[X54] 28).Sniderman AD: Type III Hyperlipoproteinemia: The Forgotten, Disregarded, Neglected, Overlooked, Ignored but Highly Atherogenic, and Highly Treatable Dyslipoproteinemia. Clin Chem, 2019; 65: 225-227 [DOI] [PubMed] [Google Scholar]

[X55] 29).Marduel M, Ouguerram K, Serre V, Bonnefont-Rousselot D, Marques-Pinheiro A, Erik Berge K, Devillers M, Luc G, Lecerf JM, Tosolini L, Erlich D, Peloso GM, Stitziel N, Nitchke P, Jais JP, French Research Network on ADH, Abifadel M, Kathiresan S, Leren TP, Rabes JP, Boileau C and Varret M: Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation. Hum Mutat, 2013; 34: 83-87 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X56] 30).Mabuchi H, Itoh H, Takeda M, Kajinami K, Wakasugi T, Koizumi J, Takeda R and Asagami C: A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism, 1989; 38: 115-119 [DOI] [PubMed] [Google Scholar]

[X57] 31).Kurosaka D, Teramoto T, Matsushima T, Yokoyama T, Yamada A, Aikawa T, Miyamoto Y and Kurokawa K: Apolipoprotein E deficiency with a depressed mRNA of normal size. Atherosclerosis, 1991; 88: 15-20 [DOI] [PubMed] [Google Scholar]

[X58] 32).Schaefer EJ, Gregg RE, Ghiselli G, Forte TM, Ordovas JM, Zech LA and Brewer HB, Jr.: Familial apolipoprotein E deficiency. J Clin Invest, 1986; 78: 1206-1219 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X59] 33).Cladaras C, Hadzopoulou-Cladaras M, Felber BK, Pavlakis G and Zannis VI: The molecular basis of a familial apoE deficiency. An acceptor splice site mutation in the third intron of the deficient apoE gene. J Biol Chem, 1987; 262: 2310-2315 [PubMed] [Google Scholar]

[X60] 34).Mak AC, Pullinger CR, Tang LF, Wong JS, Deo RC, Schwarz JM, Gugliucci A, Movsesyan I, Ishida BY, Chu C, Poon A, Kim P, Stock EO, Schaefer EJ, Asztalos BF, Castellano JM, Wyss-Coray T, Duncan JL, Miller BL, Kane JP, Kwok PY and Malloy MJ: Effects of the absence of apolipoprotein e on lipoproteins, neurocognitive function, and retinal function. JAMA Neurol, 2014; 71: 1228-1236 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X61] 35).Feussner G, Dobmeyer J, Grone HJ, Lohmer S and Wohlfeil S: A 10-bp deletion in the apolipoprotein epsilon gene causing apolipoprotein E deficiency and severe type III hyperlipoproteinemia. Am J Hum Genet, 1996; 58: 281-291 [PMC free article] [PubMed] [Google Scholar]

[X62] 36).Lohse P, Brewer HB, 3rd, Meng MS, Skarlatos SI, LaRosa JC and Brewer HB, Jr.: Familial apolipoprotein E deficiency and type III hyperlipoproteinemia due to a premature stop codon in the apolipoprotein E gene. J Lipid Res, 1992; 33: 1583-1590 [PubMed] [Google Scholar]

[X63] 37).Feussner G, Funke H, Weng W, Assmann G, Lackner KJ and Ziegler R: Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and epsilon 1/’null’ genotype. Eur J Clin Invest, 1992; 22: 599-608 [DOI] [PubMed] [Google Scholar]

[X64] 38).Feussner G and Ziegler R: Response to therapy of a type III hyperlipoproteinemic subject with the rare apolipoprotein E1 (Gly127----Asp, Arg158----Cys) variant. Clin Investig, 1992; 70: 614-617 [DOI] [PubMed] [Google Scholar]

[X65] 39).Leren TP, Strom TB and Berge KE: Variable phenotypic expression of nonsense mutation p.Thr5* in the APOE gene. Mol Genet Metab Rep, 2016; 9: 67-70 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X66] 40).Abou Khalil Y, Marmontel O, Ferrieres J, Paillard F, Yelnik C, Carreau V, Charriere S, Bruckert E, Gallo A, Giral P, Philippi A, Bluteau O, Boileau C, Abifadel M, Di-Filippo M, Carrie A, Rabes JP and Varret M: APOE Molecular Spectrum in a French Cohort with Primary Dyslipidemia. Int J Mol Sci, 2022; 23: [DOI] [PMC free article] [PubMed] [Google Scholar]

[X67] 41).Dijck-Brouwer DA, van Doormaal JJ, Kema IP, Brugman AM, Kingma AW and Muskiet FA: Discovery and consequences of apolipoprotein-epsilon(3Groningen): a G-insertion in codon 95/96 that is predicted to cause a premature stop codon. Ann Clin Biochem, 2005; 42: 264-268 [DOI] [PubMed] [Google Scholar]

[X68] 42).Tate JR, Hoffmann MM, Lovelock PK, Kesting JB and Shaw JT: Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian. Ann Clin Biochem, 2001; 38: 46-53 [DOI] [PubMed] [Google Scholar]

[X69] 43).Stephens JW, Sozen MM, Whittall RA, Caslake MJ, Bedford D, Acharya J, Hurel SJ and Humphries SE: Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem, 2005; 51: 119-124 [DOI] [PubMed] [Google Scholar]

[X70] 44).Bea AM, Larrea-Sebal A, Marco-Benedi V, Uribe KB, Galicia-Garcia U, Lamiquiz-Moneo I, Laclaustra M, Moreno-Franco B, Fernandez-Corredoira P, Olmos S, Civeira F, Martin C and Cenarro A: Contribution of APOE Genetic Variants to Dyslipidemia. Arterioscler Thromb Vasc Biol, 2023; 43: 1066-1077 [DOI] [PubMed] [Google Scholar]

[X71] 45).Smit M, de Knijff P, van der Kooij-Meijs E, Groenendijk C, van den Maagdenberg AM, Gevers Leuven JA, Stalenhoef AF, Stuyt PM, Frants RR and Havekes LM: Genetic heterogeneity in familial dysbetalipoproteinemia. The E2(lys146----gln) variant results in a dominant mode of inheritance. J Lipid Res, 1990; 31: 45-53 [PubMed] [Google Scholar]

[X72] 46).Khalil YA, Rabes JP, Boileau C and Varret M: APOE gene variants in primary dyslipidemia. Atherosclerosis, 2021; 328: 11-22 [DOI] [PubMed] [Google Scholar]

[X73] 47).Feussner G, Albanese M, Mann WA, Valencia A and Schuster H: Apolipoprotein E2 (Arg-136-->Cys), a variant of apolipoprotein E associated with late-onset dominance of type III hyperlipoproteinaemia. Eur J Clin Invest, 1996; 26: 13-23 [DOI] [PubMed] [Google Scholar]

[X74] 48).Wardell MR, Brennan SO, Janus ED, Fraser R and Carrell RW: Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. J Clin Invest, 1987; 80: 483-490 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X75] 49).Horie Y, Fazio S, Westerlund JR, Weisgraber KH and Rall SC, Jr.: The functional characteristics of a human apolipoprotein E variant (cysteine at residue 142) may explain its association with dominant expression of type III hyperlipoproteinemia. J Biol Chem, 1992; 267: 1962-1968 [PubMed] [Google Scholar]

[X76] 50).Havel RJ, Kotite L, Kane JP, Tun P and Bersot T: Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J Clin Invest, 1983; 72: 379-387 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X77] 51).Richard P, de Zulueta MP, Beucler I, De Gennes JL, Cassaigne A and Iron A: Identification of a new apolipoprotein E variant (E2 Arg142-->Leu) in type III hyperlipidemia. Atherosclerosis, 1995; 112: 19-28 [DOI] [PubMed] [Google Scholar]

[X78] 52).Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, Kaneko S and Arakawa K: Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia. Biochim Biophys Acta, 1992; 1128: 58-64 [DOI] [PubMed] [Google Scholar]

[X79] 53).Mann WA, Lohse P, Gregg RE, Ronan R, Hoeg JM, Zech LA and Brewer HB, Jr.: Dominant expression of type III hyperlipoproteinemia. Pathophysiological insights derived from the structural and kinetic characteristics of ApoE-1 (Lys146-->Glu). J Clin Invest, 1995; 96: 1100-1107 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X80] 54).Hoffer MJ, Niththyananthan S, Naoumova RP, Kibirige MS, Frants RR, Havekes LM and Thompson GR: Apolipoprotein E1-Hammersmith (Lys146-->Asn; Arg147-->Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia. Atherosclerosis, 1996; 124: 183-189 [DOI] [PubMed] [Google Scholar]

[X81] 55).van den Maagdenberg AM, de Knijff P, Stalenhoef AF, Gevers Leuven JA, Havekes LM and Frants RR: Apolipoprotein E*3-Leiden allele results from a partial gene duplication in exon 4. Biochem Biophys Res Commun, 1989; 165: 851-857 [DOI] [PubMed] [Google Scholar]

[X82] 56).Weisgraber KH, Rall SC, Jr., Innerarity TL, Mahley RW, Kuusi T and Ehnholm C: A novel electrophoretic variant of human apolipoprotein E. Identification and characterization of apolipoprotein E1. J Clin Invest, 1984; 73: 1024-1033 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X83] 57).Wintjens R, Bozon D, Belabbas K, F MB, Girardet JP, Tounian P, Jolly M, Boccara F, Cohen A, Karsenty A, Dubern B, Carel JC, Azar-Kolakez A, Feillet F, Labarthe F, Gorsky AM, Horovitz A, Tamarindi C, Kieffer P, Lienhardt A, Lascols O, Di Filippo M and Dufernez F: Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. J Lipid Res, 2016; 57: 482-491 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X84] 58).Steinmetz A, Assefbarkhi N, Eltze C, Ehlenz K, Funke H, Pies A, Assmann G and Kaffarnik H: Normolipemic dysbetalipoproteinemia and hyperlipoproteinemia type III in subjects homozygous for a rare genetic apolipoprotein E variant (apoE1). J Lipid Res, 1990; 31: 1005-1013 [PubMed] [Google Scholar]

[X85] 59).Minnich A, Weisgraber KH, Newhouse Y, Dong LM, Fortin LJ, Tremblay M and Davignon J: Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3’ (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. J Lipid Res, 1995; 36: 57-66 [PubMed] [Google Scholar]

[X86] 60).Sakuma N, Hibino T, Saeki T, Nagata T, Sato T, Okuda N, Matsunaga A and Sasaki J: Compound heterozygotes for a novel mutation, apo E1 Nagoya (Arg142Ser) and Apo E2 (Arg158Cys), with severe type III hyperlipoproteinemia and familial hypercholesterolemia. J Atheroscler Thromb, 2014; 21: 983-988 [DOI] [PubMed] [Google Scholar]

[X87] 61).Suehiro T, Yoshida K, Yamano T and Ohno F: Identification and characterization of a new variant of apolipoprotein E (apo E-Kochi). Jpn J Med, 1990; 29: 587-594 [DOI] [PubMed] [Google Scholar]

[X88] 62).Hidaka H, Tozuka M, Hidaka E, Yamauchi K, Ota H, Honda T and Katsuyama T: Characterization of an apolipoprotein E3 variant (Arg 145-->His) associated with mild hypertriglyceridemia. Ann Clin Lab Sci, 2001; 31: 163-170 [PubMed] [Google Scholar]

[X89] 63).Lohse P, Mann WA, Stein EA and Brewer HB, Jr.: Apolipoprotein E-4Philadelphia (Glu13----Lys,Arg145----Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia. J Biol Chem, 1991; 266: 10479-10484 [PubMed] [Google Scholar]

[X90] 64).Abou Ziki MD, Strulovici-Barel Y, Hackett NR, Rodriguez-Flores JL, Mezey JG, Salit J, Radisch S, Hollmann C, Chouchane L, Malek J, Zirie MA, Jayyuosi A, Gotto AM, Jr. and Crystal RG: Prevalence of the apolipoprotein E Arg145Cys dyslipidemia at-risk polymorphism in African-derived populations. Am J Cardiol, 2014; 113: 302-308 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X91] 65).de Villiers WJ, van der Westhuyzen DR, Coetzee GA, Henderson HE and Marais AD: The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance. Arterioscler Thromb Vasc Biol, 1997; 17: 865-872 [DOI] [PubMed] [Google Scholar]

[X92] 66).Okubo M, Aoyama Y, Harada K, Fukawa M, Tsukada T, Mokuno H, Yamada N and Murase T: A novel apolipoprotein E2 variant, E2Toranomon (Q187E), identified in a type III hyperlipoproteinemia patient with coronary atherosclerosis. Atherosclerosis, 1998; 140: 187-190 [DOI] [PubMed] [Google Scholar]

[X93] 67).Hayakawa M, Okubo M, Katori H, Nagahama K, Murase T, Kobayashi T, Tanaka S, Nakanishi K, Odawara M, Matsushita H and Yamada A: A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy. Am J Kidney Dis, 2002; 39: E15 [DOI] [PubMed] [Google Scholar]

[X94] 68).Saito T, Sato H, Kudo K, Oikawa S, Shibata T, Hara Y, Yoshinaga K and Sakaguchi H: Lipoprotein glomerulopathy: glomerular lipoprotein thrombi in a patient with hyperlipoproteinemia. Am J Kidney Dis, 1989; 13: 148-153 [DOI] [PubMed] [Google Scholar]

[X95] 69).Saito T, Matsunaga A and Oikawa S: Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis, 2006; 47: 199-211 [DOI] [PubMed] [Google Scholar]

[X96] 70).Matsunaga A and Saito T: Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia. Clin Exp Nephrol, 2014; 18: 220-224 [DOI] [PubMed] [Google Scholar]

[X97] 71).Saito T and Matsunaga A: Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis. Kidney Int, 2014; 85: 243-245 [DOI] [PubMed] [Google Scholar]

[X98] 72).Oikawa S, Matsunaga A, Saito T, Sato H, Seki T, Hoshi K, Hayasaka K, Kotake H, Midorikawa H, Sekikawa A, Hara S, Abe K, Toyota T, Jingami H, Nakamura H and Sasaki J: Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 [DOI] [PubMed] [Google Scholar]

[X99] 73).Konishi K, Saruta T, Kuramochi S, Oikawa S, Saito T, Han H, Matsunaga A and Sasaki J: Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron, 1999; 83: 214-218 [DOI] [PubMed] [Google Scholar]

[X100] 74).Ogawa T, Maruyama K, Hattori H, Arai H, Kondoh I, Egashira T, Watanabe T, Kobayashi Y and Morikawa A: A new variant of apolipoprotein E (apo E Maebashi) in lipoprotein glomerulopathy. Pediatr Nephrol, 2000; 14: 149-151 [DOI] [PubMed] [Google Scholar]

[X101] 75).Xie W, Xie Y, Lin Z, Xu X and 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; 14: 41 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X102] 76).Sam R, Wu H, Yue L, Mazzone T, Schwartz MM, Arruda JA, Dunea G and Singh AK: Lipoprotein glomerulopathy: a new apolipoprotein E mutation with enhanced glomerular binding. Am J Kidney Dis, 2006; 47: 539-548 [DOI] [PubMed] [Google Scholar]

[X103] 77).Kinomura M, Sugiyama H, Saito T, Matsunaga A, Sada KE, Kanzaki M, Takazawa Y, Maeshima Y, Yanai H and Makino H: A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy. Nephrol Dial Transplant, 2008; 23: 751-756 [DOI] [PubMed] [Google Scholar]

[X104] 78).Tsimihodimos V and Elisaf M: Lipoprotein glomerulopathy. Curr Opin Lipidol, 2011; 22: 262-269 [DOI] [PubMed] [Google Scholar]

[X105] 79).Luo B, Huang F, Liu Q, Li X, Chen W, Zhou SF and Yu X: Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol, 2008; 28: 347-353 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X106] 80).Yokochi A, Matsunaga A, Kanemoto K, Tominaga N, Uda S and Saito T: Lipoprotein glomerulopathy with a novel apolipoprotein E variant, APOE Kanto (Asp 151dup). CEN Case Rep, 2024; [DOI] [PMC free article] [PubMed] [Google Scholar]

[X107] 81).Bomback AS, Song H, D’Agati VD, Cohen SD, Neal A, Appel GB and Rovin BH: A new apolipoprotein E mutation, apoE Las Vegas, in a European-American with lipoprotein glomerulopathy. Nephrol Dial Transplant, 2010; 25: 3442-3446 [DOI] [PubMed] [Google Scholar]

[X108] 82).Wu H, Yang Y and Hu Z: The Novel Apolipoprotein E Mutation ApoE Chengdu (c.518T>C, p.L173P) in a Chinese Patient with Lipoprotein Glomerulopathy. J Atheroscler Thromb, 2018; 25: 733-740 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X109] 83).Ando M, Sasaki J, Hua H, Matsunaga A, Uchida K, Jou K, Oikawa S, Saito T and Nihei H: A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int, 1999; 56: 1317-1323 [DOI] [PubMed] [Google Scholar]

[X110] 84).Mitani A, Ishigami M, Watase K, Minakata T and Yamamura T: A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy. J Atheroscler Thromb, 2011; 18: 531-535 [DOI] [PubMed] [Google Scholar]

[X111] 85).Tokura T, Itano S, Kobayashi S, Kuwabara A, Fujimoto S, Horike H, Satoh M, Komai N, Tomita N, Matsunaga A, Saito T, Sasaki T and Kashihara N: A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. J Atheroscler Thromb, 2011; 18: 536-541 [DOI] [PubMed] [Google Scholar]

[X112] 86).Hagiwara M, Yamagata K, Matsunaga T, Arakawa Y, Usui J, Shimizu Y, Aita K, Nagata M, Koyama A, Zhang B, Mastunaga A, Saku K and Saito T: A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy. Nephrol Dial Transplant, 2008; 23: 381-384 [DOI] [PubMed] [Google Scholar]

[X113] 87).Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, Tsuji E, Moriyama K, Koga T, Arakawa K, Oikawa S, Saito T, Kita T and Doi T: A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int, 1999; 56: 421-427 [DOI] [PubMed] [Google Scholar]

[X114] 88).Li Y, Chen J, Zou Y, Wang W and Li G: Lipoprotein glomerulopathy resulting from compound heterogeneous mutations of APOE gene: A case report. Medicine (Baltimore), 2022; 101: e28718 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X115] 89).Cheung CY, Chan AO, Chan YH, Lee KC, Chan GP, Lau GT, Shek CC, Chau KF and Li CS: A rare cause of nephrotic syndrome: lipoprotein glomerulopathy. Hong Kong Med J, 2009; 15: 57-60 [PubMed] [Google Scholar]

[X116] 90).Kodera H, Mizutani Y, Sugiyama S, Miyata T, Ehara T, Matsunaga A and Saito T: A Case of Lipoprotein Glomerulopathy with apoE Chicago and apoE (Glu3Lys) Treated with Fenofibrate. Case Rep Nephrol Dial, 2017; 7: 112-120 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X117] 91).Wang R, Zhao C, Chen W, Liu Z and Xie F: A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports. J Med Case Rep, 2022; 16: 78 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X118] 92).Ku M, Tao C, Zhou AA, Cheng Y and Wan QJ: A novel apolipoprotein E mutation (p.Arg150Cys) in a Chinese patient with lipoprotein glomerulopathy. Chin Med J (Engl), 2019; 132: 237-239 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X119] 93).Toyota K, Hashimoto T, Ogino D, Matsunaga A, Ito M, Masakane I, Degawa N, Sato H, Shirai S, Umetsu K, Tamiya G, Saito T and Hayasaka K: A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet, 2013; 58: 254-258 [DOI] [PubMed] [Google Scholar]

[X120] 94).Li MS, Li Y, Liu Y, Zhou XJ and Zhang H: An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy. Front Med (Lausanne), 2022; 9: 905007 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X121] 95).Ishigaki Y, Oikawa S, Suzuki T, Usui S, Magoori K, Kim DH, Suzuki H, Sasaki J, Sasano H, Okazaki M, Toyota T, Saito T and Yamamoto TT: Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice. J Biol Chem, 2000; 275: 31269-31273 [DOI] [PubMed] [Google Scholar]

[X122] 96).Wu H, Yang J, Liu YQ, Lei S, Yang M, Yang Z, Yang Y and Hu Z: Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice. J Transl Med, 2021; 19: 97 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X123] 97).Saito T, Matsunaga A, Fukunaga M, Nagahama K, Hara S and Muso E: Apolipoprotein E-related glomerular disorders. Kidney Int, 2020; 97: 279-288 [DOI] [PubMed] [Google Scholar]

[X124] 98).Kawanishi K, Sawada A, Ochi A, Moriyama T, Mitobe M, Mochizuki T, Honda K, Oda H, Nishikawa T and Nitta K: Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature. Case Rep Nephrol Urol, 2013; 3: 128-135 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X125] 99).Kato T, Ushiogi Y, Yokoyama H, Hara S, Matsunaga A, Muso E and Saito T: A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes. CEN Case Rep, 2019; 8: 106-111 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X126] 100).Sakatsume M, Kadomura M, Sakata I, Imai N, Kondo D, Osawa Y, Shimada H, Ueno M, Miida T, Nishi S, Arakawa M and Gejyo F: Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity. Kidney Int, 2001; 59: 1911-1918 [DOI] [PubMed] [Google Scholar]

[X127] 101).Fukunaga M, Nagahama K, Aoki M, Shimizu A, Hara S, Matsunaga A, Muso E and Saito T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2. Case Rep Nephrol Dial, 2018; 8: 45-55 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X128] 102).Hirashima H, Komiya T, Toriu N, Hara S, Matsunaga A, Saito T and Muso E: A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka. Clin Nephrol Case Stud, 2018; 6: 45-51 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X129] 103).Koshino A, Takaeda C, Matsuno T, Kitajima S, Iwata Y, Sakai N, Nagahama K, Niida Y, Saito T, Yokoyama H and Wada T: Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits. Case Rep Nephrol Dial, 2022; 12: 96-104 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X130] 104).Yamanouchi Y, Arinami T, Tsuchiya S, Miyazaki R, Takaki H, Takano T and Hamaguchi H: Apolipoprotein E5 and E7 in apparently healthy Japanese males: frequencies and relation to plasma lipid levels. Jpn J Hum Genet, 1994; 39: 315-324 [DOI] [PubMed] [Google Scholar]

[X131] 105).Dong LM, Yamamura T, Tajima S and Yamamoto A: Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3----Lys) and its binding to low density lipoprotein receptors. Biochem Biophys Res Commun, 1992; 187: 1180-1186 [DOI] [PubMed] [Google Scholar]

[X132] 106).Tajima S, Yamamura T and Yamamoto A: Analysis of apolipoprotein E5 gene from a patient with hyperlipoproteinemia. J Biochem, 1988; 104: 48-52 [DOI] [PubMed] [Google Scholar]

[X133] 107).Kobayashi J, Shirai K, Murano T, Misawa Y, Tashiro J, Yoshida T and Shinomiya M: A case of hyperlipidemia with homozygous apolipoprotein E5 (Glu3-->Lys). Biochim Biophys Acta, 2002; 1583: 117-121 [DOI] [PubMed] [Google Scholar]

[X134] 108).Orth M, Weng W, Funke H, Steinmetz A, Assmann G, Nauck M, Dierkes J, Ambrosch A, Weisgraber KH, Mahley RW, Wieland H and Luley C: Effects of a frequent apolipoprotein E isoform, ApoE4Freiburg (Leu28-->Pro), on lipoproteins and the prevalence of coronary artery disease in whites. Arterioscler Thromb Vasc Biol, 1999; 19: 1306-1315 [DOI] [PubMed] [Google Scholar]

[X135] 109).Kamboh MI, Aston CE, Perez-Tur J, Kokmen E, Ferrell RE, Hardy J and DeKosky ST: A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer’s disease. Neurosci Lett, 1999; 263: 129-132 [DOI] [PubMed] [Google Scholar]

[X136] 110).Argyri L, Dafnis I, Theodossiou TA, Gantz D, Stratikos E and Chroni A: Molecular basis for increased risk for late-onset Alzheimer disease due to the naturally occurring L28P mutation in apolipoprotein E4. J Biol Chem, 2014; 289: 12931-12945 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X137] 111).Fan K, Francis L, Aslam MM, Bedison MA, Lawrence E, Acharya V, Snitz BE, Ganguli M, DeKosky ST, Lopez OL, Feingold E and Kamboh MI: Investigation of the independent role of a rare APOE variant (L28P; APOE*4Pittsburgh) in late-onset Alzheimer disease. Neurobiol Aging, 2023; 122: 107-111 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X138] 112).Ruzicka V, Marz W, Russ A, Fisher E, Mondorf W and Gross W: Characterization of the gene for apolipoprotein E5-Frankfurt (Gln81->Lys, Cys112->Arg) by polymerase chain reaction, restriction isotyping, and temperature gradient gel electrophoresis. Electrophoresis, 1993; 14: 1032-1037 [DOI] [PubMed] [Google Scholar]

[X139] 113).Wardell MR, Rall SC, Jr., Schaefer EJ, Kane JP and Weisgraber KH: Two apolipoprotein E5 variants illustrate the importance of the position of additional positive charge on receptor-binding activity. J Lipid Res, 1991; 32: 521-528 [PubMed] [Google Scholar]

[X140] 114).Yamanouchi Y, Takano T, Hamaguchi H and Tokunaga K: A novel apolipoprotein E5 variant with a 24-bp insertion causing hyperlipidemia. J Hum Genet, 2001; 46: 633-639 [DOI] [PubMed] [Google Scholar]

[X141] 115).Nguyen TT, Kruckeberg KE, O’Brien JF, Ji ZS, Karnes PS, Crotty TB, Hay ID, Mahley RW and O’Brien T: Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]. J Clin Endocrinol Metab, 2000; 85: 4354-4358 [DOI] [PubMed] [Google Scholar]

[X142] 116).Faivre L, Saugier-Veber P, Pais de Barros JP, Verges B, Couret B, Lorcerie B, Thauvin C, Charbonnier F, Huet F, Gambert P, Frebourg T and Duvillard L: Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation. Eur J Hum Genet, 2005; 13: 1186-1191 [DOI] [PubMed] [Google Scholar]

[X143] 117).Solanas-Barca M, de Castro-Oros I, Mateo-Gallego R, Cofan M, Plana N, Puzo J, Burillo E, Martin-Fuentes P, Ros E, Masana L, Pocovi M, Civeira F and Cenarro A: Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia. Atherosclerosis, 2012; 222: 449-455 [DOI] [PubMed] [Google Scholar]

[X144] 118).Okorodudu DE, Crowley MJ, Sebastian S, Rowell JV and Guyton JR: Inherited lipemic splenomegaly and the spectrum of apolipoprotein E p.Leu167del mutation phenotypic variation. J Clin Lipidol, 2013; 7: 566-572 [DOI] [PubMed] [Google Scholar]

[X145] 119).Hoffmann MM, Scharnagl H, Koster W, Winkler K, Wieland H and Marz W: Apolipoprotein E1 Baden (Arg(180)-->Cys). A new apolipoprotein E variant associated with hypertriglyceridemia. Clin Chim Acta, 2001; 303: 41-48 [DOI] [PubMed] [Google Scholar]

[X146] 120).Moriyama K, Sasaki J, Takada Y, Arakawa F, Matsunaga A, Ito Y and Arakawa K: Characterization of a novel variant of apolipoprotein E, E2 Fukuoka (Arg-224 --> Gln) in a hyperlipidemic patient with xanthomatosis. Biochim Biophys Acta, 1996; 1301: 185-190 [DOI] [PubMed] [Google Scholar]

[X147] 121).Wardell MR, Rall SC, Jr., Brennan SO, Nye ER, George PM, Janus ED and Weisgraber KH: Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity. J Lipid Res, 1990; 31: 535-543 [PubMed] [Google Scholar]

[X148] 122).van den Maagdenberg AM, Weng W, de Bruijn IH, de Knijff P, Funke H, Smelt AH, Gevers Leuven JA, van’t Hooft FM, Assmann G, Hofker MH and et al.: Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia. Am J Hum Genet, 1993; 52: 937-946 [PMC free article] [PubMed] [Google Scholar]

[X149] 123).Yanagi K, Yamashita S, Hiraoka H, Ishigami M, Kihara S, Hirano K, Sakai N, Nozaki S, Funahashi T, Kameda-Takemura K, Kubo M, Tokunaga K and Matsuzawa Y: Increased serum remnant lipoproteins in patients with apolipoprotein E7 (apo E Suita). Atherosclerosis, 1997; 131: 49-58 [DOI] [PubMed] [Google Scholar]

[X150] 124).Feussner G, Scharnagl H, Scherbaum C, Acar J, Dobmeyer J, Lohrmann J, Wieland H and Marz W: Apolipoprotein E5 (Glu212-->Lys): increased binding to cell surface proteoglycans but decreased uptake and lysosomal degradation in cultured fibroblasts. J Lipid Res, 1996; 37: 1632-1645 [PubMed] [Google Scholar]

[X151] 125).Scacchi R, De Stefano GF, Ruggeri M and Corbo RM: Genetic variation at apolipoprotein E locus in Ethiopia: An E5 variant corresponds to two different mutant alleles: E*5 (Glu212Lys) and E*5 (Gln204Lys; Cys112Arg). Human Biology, 2003; 75: 293-300 [DOI] [PubMed] [Google Scholar]

[X152] 126).Masoodi TA, Al Shammari SA, Al-Muammar MN and Alhamdan AA: Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer’s Disease. Neurol Res Int, 2012; 2012: 480609 [DOI] [PMC free article] [PubMed] [Google Scholar]

[X153] 127).Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG and Frikke-Schmidt R: APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement, 2020; 16: 1624-1637 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features

Akira Matsunaga

Takao Saito

Abstract

Introduction

Lipoproteins and ApoE

Function of ApoE

Fig.1 Schematic diagram of apoE’s function on triglyceride-rich lipoprotein particles or remnant particles inside and outside of blood vessels.

Structure of ApoE

Fig.2. Human apoE model structure with triglyceride-rich lipoprotein particle.

Common Isoforms

Fig.3. Three major phenotypes (genotypes) of apoE.

APOE gene

Fig.4. APOE gene and apoE protein .

Supplementary Table 1. Reported APOE variants sorted by DNA sequence.

Familial Type III Hyperlipoproteinemia (HLP)

APOE Deficiency

Table 1. List of APOE deficiencies.

Familial type III HLP not due to APOE2 Homozygotes

Fig.5. Schematic representation of APOE variants with familial type III HLP (top) and LPG (bottom) .

Table 2. Variants of familial type III HLP not due to APOE2 homozygotes or APOE deficiency.

Lipoprotein Glomerulopathy (LPG)

Table 3. Variants of LPG and APOE Toyonaka.

ApoE2 Homozygote Glomerulopathy and APOE Toyonaka (Ser197Cys)

APOE Variants Associated with other Lipid Abnormalities

Table 4. Variants associated with other lipid abnormalities.

Other Reported APOE Variants

Table 5. Other reported APOE variants .

Conclusion

Conflict of Interest

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features

Akira Matsunaga

Takao Saito

Abstract

Introduction

Lipoproteins and ApoE

Function of ApoE

Fig.1 Schematic diagram of apoE’s function on triglyceride-rich lipoprotein particles or remnant particles inside and outside of blood vessels.

Structure of ApoE

Fig.2. Human apoE model structure with triglyceride-rich lipoprotein particle.

Common Isoforms

Fig.3. Three major phenotypes (genotypes) of apoE.

APOE gene

Fig.4. APOE gene and apoE protein .

Supplementary Table 1. Reported APOE variants sorted by DNA sequence.

Familial Type III Hyperlipoproteinemia (HLP)

APOE Deficiency

Table 1. List of APOE deficiencies.

Familial type III HLP not due to APOE2 Homozygotes

Fig.5. Schematic representation of APOE variants with familial type III HLP (top) and LPG (bottom) .

Table 2. Variants of familial type III HLP not due to APOE2 homozygotes or APOE deficiency.

Lipoprotein Glomerulopathy (LPG)

Table 3. Variants of LPG and APOE Toyonaka.

ApoE2 Homozygote Glomerulopathy and APOE Toyonaka (Ser197Cys)

APOE Variants Associated with other Lipid Abnormalities

Table 4. Variants associated with other lipid abnormalities.

Other Reported APOE Variants

Table 5. Other reported APOE variants .

Conclusion

Conflict of Interest

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases