Clin Exp Nephrol DOI 10.1007/s10157-013-0918-1
REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia Akira Matsunaga • Takao Saito
Received: 4 October 2013 / Accepted: 23 October 2013 Ó Japanese Society of Nephrology 2014
Abstract Apolipoprotein E (ApoE) serves as a ligand for the low-density lipoprotein (LDL) receptor and cell surface receptors of the LDL receptor gene family. More than 10 different causative apoE mutations associated with lipoprotein glomerulopathy (LPG) have been reported. ApoE polymorphisms including three common phenotypes (E2, E3, E4), and a variety of rare mutations can affect blood cholesterol and triglyceride levels. The N-terminal domain of apoE is folded into a four-helix bundle of amphipathic a-helices, and contains the receptor-binding domain in which most apoE mutations that cause LPG or dominant mode of type III hyperlipoproteinemia (HL) are located. No single apoE mutation has been reported that causes both LPG and the dominant mode of type III HL. Keywords Apolipoprotein E Lipoprotein glomerulopathy Type III hyperlipoproteinemia Dominant mode Mutation
Introduction Lipoprotein glomerulopathy (LPG) is a rare renal disorder, characterized by the presence of lipoprotein thrombi in the glomeruli, an abnormal plasma lipoprotein profile that resembles type III hyperlipoproteinemia (HL), and a A. Matsunaga (&) Department of Laboratory Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan e-mail: [email protected] T. Saito General Medical Research Center, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
marked increase in serum apolipoprotein E (apoE) concentrations. Rare APOE mutations may contribute to the pathogenesis of the disease [1]. Since it was first described by Saito et al. in 1989 [2], the disease has been reported in approximately 150 patients, most of them in Japan, China, and other East Asian countries. Few cases have been reported in the United States or Europe. The purpose of this review was to understand the type of APOE mutations associated with LPG by comparing the differences in disease caused by a variety of APOE mutations with those of type III HL.
ApoE and polymorphisms ApoE is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types including the brain, kidney, adipocytes, and macrophages. It serves as a ligand for the receptor-mediated uptake of lipoproteins through the low-density lipoprotein (LDL) receptor, cell surface receptors of the LDL receptor gene family, and heparan sulfate proteoglycans. ApoE is normally present in the plasma at 5 mg/dl, and is one of the major apolipoproteins of cerebrospinal fluid and the central nervous system. It associates with chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL). ApoE knockout mice, which accumulate cholesterol-rich lipoproteins such as IDL and b-VLDL causing rapid atherosclerosis in the body, are used around the world as an animal model of arteriosclerosis [3]. The human APOE gene maps to chromosome 19 in a cluster with APOC1, APOC4, and APOC2 genes. ApoE is a glycoprotein with a molecular weight of 34 kDa consisting of 299 amino residues. Newly synthesized apoE is modified by O-glycosylation at Thr194, and this post-
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Clin Exp Nephrol
2/2 3/3 4/4 2/3 2/4 3/4
E4 E3 E2
Fig. 1 Isoelectric focusing and immunoblot analysis of the apoE phenotype. The six lanes show the apoE phenotypes E2/E2, E3/E3, E4/E4, E2/E3, E2/E4, and E3/E4, respectively
translational modification enables apoE to display several non-genetic isoforms contributed by differential sialylation [4]. APOE polymorphisms can lead to variations in blood cholesterol and triglyceride levels, and, typically, three different phenotypes (E2, E3, E4) have been determined by isoelectric focusing and the immunoblotting of delipidated neuraminidase-treated plasma (Fig. 1). ApoE3 is the predominant isoform. ApoE4 differs from apoE3 by an amino acid substitution at position 112 (C112R), while apoE2 has a substitution at position 158 (R158C). APOE genotyping is mainly performed by polymerase chain reaction-based restriction enzyme digestion and restriction fragment length polymorphism analysis on polyacrylamide gels [5]; the presence of the three most common APOE alleles (e2, e3, and e4) is determined by this method. ApoE4 is associated with increased cholesterol levels, thus enhancing the risk of heart disease [6]. In addition, E4/E4 individuals have a very high risk for developing Alzheimer’s disease [7]. Most patients with type III HL are homozygous for apoE2.
ApoE structure and dysbetalipoproteinemia ApoE contains two structural domains, an N-terminal and a C-terminal domain, each associated with a specific function. The N-terminal domain contains the lipoprotein receptor binding region and the C-terminal domain contains the major lipid binding elements. Most of the secondary structure, about 62 %, consists of amphipathic a-helices, while the remainder is made up of b-sheets
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(9 %), b-turns (11 %), and random structures (18 %). Receptor binding is important for the cellular uptake of lipoproteins, and is believed to occur because of the ionic interactions between the basic residues of apoE and the acidic residues (from aspartic and glutamic acids) of the lipid receptor. The strongest lipid binding occurs in the carboxyl terminal portion, between residues 244–272, and the five arginine and three lysine residues between residues 140–160 are essential for binding to the LDL receptor [8]. X-ray crystallography studies show that the N-terminal domain is folded into a four-helix bundle of amphipathic a-helices, containing the receptor binding region [9]. Helix 4 in apoE2 contains a critical salt bridge rearrangement that reduces the positive potential of the boxed LDL receptor binding side. Asp-154 changes its ionic interaction to Arg150 in apoE2 because of the Cys-158 substitution, pulling the side chain of Arg-150 out of the positive potential cloud and reducing its potential [10]. The apoE2 isoform shows \2 % of the normal receptor binding activity and is associated with a recessive mode of inheritance of type III HL. In this recessive form, the development of overt hyperlipidemia requires the inheritance of two alleles of APOE 2. The occurrence of the defective alleles is necessary but not usually sufficient to induce type III HL. Moreover, most apo E2/E2 subjects are either normolipidemic or even hypocholesterolemic. Thus, the development of the recessive form of overt hyperlipidemia involves other genetic, hormonal, or environmental influences that, in combination with the defective receptor binding of apoE, precipitate the development of hypertriglyceridemia and hypercholesterolemia. The secondary factors include diabetes, hypothyroidism, low-estrogen conditions, obesity, and age. Type III HL is characterized by xanthomas, and elevated plasma cholesterol and triglyceride levels, and is associated with premature atherosclerosis. Besides apoE2, which is associated with a recessive form of type III HL, a variety of rare naturally occurring APOE mutations have also been described that are associated with the dominant mode of inheritance of type III HL expressed at an early age (Fig. 2) [11–16]. The common feature of these dominant mutations is that they involve substitutions of basic residues at positions 136, 142, 145, 146, and 147. Eight of 14 mutations associated with the dominant mode of type III HL involve changes of arginine, and four lead to changes of lysine. Most of these amino acids are located within the receptor binding domain (residues 136–150) of apoE [10] or the first heparin binding domain (residues 142–147) of the molecule. Rare APOE mutations have also been identified which are associated either with LPG, or with the development of hypertriglyceridemia or hypercholesterolemia. With the exception of apoE5 (E3K), all mutations causing hypertriglyceridemia are located within the C-terminal domain of apoE—apoE1 Baden (R158C/R180C),
Clin Exp Nephrol Fig. 2 Schematic representation of apoE mutations with LPG (bottom) and dominant type III hyperlipoproteinemia (top). Mutations that cause both diseases are concentrated in the LDL receptor binding region (amino acids 136 to 150). However, the mutations that cause dominant type III hyperlipoproteinemia were not causative of lipoprotein glomerulopathy
ApoE2 (R145C)
ApoE2 (R136C) ApoE2 (R136S)
ApoE2 (R142L)
Dominant type III hyperlipoproteinemia
ApoE4 (G13K, R145K)
ApoE3 Leiden (partial duplication of 21 nucleotides 121-127) ApoE1 (G127D, R158C)
1
ApoE4 (G13K, R145K)
ApoE3 (C112R, R142C) ApoE2 (K146Q) ApoE1 Harrisburg (K146E) ApoE3’ Kochi (R145H) ApoE1 Hammersmith (K146N, R147W)
Receptor binding
ApoE1 (K164E)
Hinge region
136 150
Lipid binding 244 272
299
NH2
COOH
ApoE2 Kyoto (R25C)
Arg or Cys (112)
Arg61
Glu255
Arg or Cys (158)
ApoE2 Tsukuba (R114C)
ApoE2 Kanto (D151dupD) ApoE2 Las Vegas (A152D)
Lipoprotein glomerulopathy
ApoE2 Sendai (R145P)
ApoE1 (156-173del)
ApoE1 Tokyo/Maebashi (141-143del)
ApoE2 Osaka/Kurashiki (R158P)
ApoE2 Chicago (R147P) ApoE2 Okayama (R150G) ApoE2 Modena (R150C) ApoE2 Guangzhou (R150P)
apoE2 Dunedin (R228C), apoE2 (V236E), apoE3 (C112R/ R251G), and apoE7 Suita (E244R/E245R) [17–20].
Table 1 Differences between lipoprotein glomerulopathy and type III hyperlipoproteinemia Factor
APOE mutations and lipoprotein glomerulopathy LPG is a rare disorder, representing a unique entity of renal lipidosis, characterized by proteinuria, renal insufficiency, and disturbances in lipoprotein metabolism closely related to those observed in type III HL, with a marked increase in serum apoE concentrations. It also has the peculiar histopathologic characteristics of lipoprotein thrombi. Evidence demonstrating a clear association between common apoE2 and LPG are very limited [21]. Rare mutations in the APOE gene may contribute to the pathogenesis of the disease [1]. Notably, although LPG and type III HL phenotypes are similar, they are different diseases (Table 1). Several APOE mutations associated with LPG have been reported in Asian patient populations, the most common being apoE Sendai (R145P, a missense mutation substituting proline for arginine at position 145) [22], apoE Kyoto (R25C, a missense mutation substituting arginine for cysteine at position 25) [23], and apoE Tokyo/Maebashi (an in-frame deletion of Leu141 to Lys143del) (Table 2; Fig. 2) [24]. ApoE Sendai (R145P) is predominantly found in eastern Japan, and was recently identified in 13 LPG patients from nine unrelated families in this area [25]. It has not been reported in China. On the other hand, apoE Kyoto (R25C), first seen in Japanese patients, has been
Dyslipidemia Cutaneous xanthomas Atherosclerosis Renal involvement Genetics
Penetrance Distribution of patients
Disease Lipoprotein glomerulopathy
Type III hyperlipoproteinemia
Mild to moderate Absent
Severe Usually present
Absent Always present Heterozygosity for rare APOE mutations Incomplete Mainly in Japan and China
Usually present Rare Homozygosity of apoE2, heterozygosity for rare APOE mutations Incomplete Worldwide
reported in European, US, Japanese, and Chinese populations, while apoE Tokyo/Maebashi (141-143del) was identified in both Japanese and Chinese individuals. Recently, apoE Kyoto (R25C) was found in 35 patients from 31 unrelated Chinese Han families with LPG, and 28 asymptomatic relatives [26]. Several different APOE mutations, including apoE Tsukuba (R114C), apoE Chicago (R147P), apoE Okayama (R150G), apoE Modena (R150G), apoE Guangzhou (R150P), apoE Las Vegas (A152D), apoE Osaka/Kurashiki (R158P), and apoE1(156-173del) have also been discovered in patients with LPG (Table 2; Fig. 2) [27–35]. All these studies suggested that LPG may be a dominant
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Clin Exp Nephrol Table 2 APOE mutations found in lipoprotein glomerulopathy Protein sequence changea
Mutation
Genomic changeb
ApoE phenotypes
References
apoE Kyoto (R25C)
p.R43C
c.61G[T
E2/E4, E2/E3
[23]
apoE Tsukuba (R114C)
p.R132C
c.394C[T
E2/E3
[27]
apoE Tokyo/Maebashi (141-143del/142-144del)
p.159_161delLRK/
c.475_483del9/
E1/E3
[24]
p.160_162delRKL
c.480_488del9
apoE Sendai (R145P)
p.R163P
c.488G[C
E2/E3, E2/E4
[22]
apoE Chicago (R147P)
p.R165P
c.494G[C
E2/E3c
[28]
apoE Okayama (R150G)
p.R168G
c.502C[G
E2/E3
[29]
apoE Modena (R150C)d
p.R168C
c.502C[T
E1/E2c
[30]
apoE Guangzhou (R150P)
p.R168P
c.503G[C
E2/E3c
[31]
apoE Kanto (D151dupD)
e
p.D169dupD
c.508-510dupGAT
E2/E3
apoE Las Vegas (A152D) apoE1 (156-173del)
p.A170D p.174_191del
c.509C[A c.520_573del
E2/E3c E1/E3
[32] [33]
apoE Osaka/Kurashiki (R158P)
p.R176P
c.527G[C
E2/E3
[34, 35]
apoE Hong Kong (D230Y)f
p.D248Y
c.742G[T
E2/E4 or E3/E3c
[37]
a
p. represents protein sequence, and the translation initiator Methionine is numbered ?1
b
c. represents coding DNA sequence, and nucleotide 1 is the A of the ATG-translation initiation codon
c
Speculative phenotype
d
Homozygous E2/E2 and heterozygosis for apoE Modena was documented
e
Unpublished case
f
DNA analysis identified both apoE Kyoto and apoE Hong Kong
inherited disease with incomplete penetrance. Eight of 12 mutations with LPG were changes of arginine, and most were located in the LDL receptor binding region, suggesting that binding of the mutated apoE to the LDL receptor may be affected because of the altered threedimensional structure of apoE. ApoE Sendai (R145P) and apoE Kyoto (R25C) have also been shown to be defective in binding to the LDL receptor [23, 36]. As shown in Fig. 2, most APOE mutations associated with the dominant mode of type III HL are located between residues 136 and 146, compared with most LPG-associated APOE mutations between residues 141 and 158. No mutation related to LPG or the dominant mode of type III HL has been identified in the C-terminal domain. Missense mutations substituting histidine, lysine, or cysteine for arginine at residue 145 cause the dominant mode of type III HL, and a mutation substituting proline at residue 145 (apoE Sendai) causes LPG. Mutations substituting glycine, cysteine, or proline for arginine at residue 150 cause LPG, while mutations substituting glutamine, glutamic acid, or asparagine for arginine at residue 145 cause the dominant mode of type III HL. Proline is established as a potent breaker of both a-helical and b-sheet structures in soluble proteins, and missense mutations substituting proline for arginine at positions 145, 147, 150 or 158 induce LPG. No single APOE mutation has been found to cause both LPG and the dominant mode of type III HL.
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Conflict of interest interest exists.
The authors have declared that no conflict of
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23. Matsunaga A, Sasaki J, Komatsu T, Kanatsu K, Tsuji E, Moriyama K, et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999;56(2): 421–7 (PubMed PMID: 10432380). 24. Konishi K, Saruta T, Kuramochi S, Oikawa S, Saito T, Han H, et al. Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83(3):214–8 (PubMed PMID: 10529627). 25. Toyota K, Hashimoto T, Ogino D, Matsunaga A, Ito M, Masakane I, et al. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy. J Hum Genet. 2013;58(5):254–8 (PubMed PMID: 23407349). 26. Hu Z, Huang S, Wu Y, Liu Y, Liu X, Su D, et al (2013) Hereditary features, treatment, and prognosis of the lipoprotein glomerulopathy in patients with the APOE Kyoto mutation. Kidney Int. (PubMed PMID: 24025644). 27. Hagiwara M, Yamagata K, Matsunaga T, Arakawa Y, Usui J, Shimizu Y, et al. A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy. Nephrol Dial Transplant. 2008;23(1):381–4 (PubMed PMID: 17967799). 28. Sam R, Wu H, Yue L, Mazzone T, Schwartz MM, Arruda JA, et al. Lipoprotein glomerulopathy: a new apolipoprotein E mutation with enhanced glomerular binding. Am J Kidney Dis. 2006;47(3):539–48 (PubMed PMID: 16490634). 29. Kinomura M, Sugiyama H, Saito T, Matsunaga A, Sada KE, Kanzaki M, et al. A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy. Nephrol Dial Transplant. 2008;23(2):751–6 (PubMed PMID: 18045818). 30. Cautero N, Di Benedetto F, De Ruvo N, Montalti R, Guerrini GP, Ballarin R, et al. Novel genetic mutation in apolipoprotein E2 homozygosis and its implication in organ donation: a case report. Transplant Proc. 2010;42(4):1349–51 (PubMed PMID: 20534298). 31. Luo B, Huang F, Liu Q, Li X, Chen W, Zhou SF, et al. Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol. 2008;28(2):347–53 (PubMed PMID: 18046082. Pubmed Central PMCID: 2785906). 32. Bomback AS, Song H, D’Agati VD, Cohen SD, Neal A, Appel GB, et al. A new apolipoprotein E mutation, apoE Las Vegas, in a European–American with lipoprotein glomerulopathy. Nephrol Dial Transplant. 2010;25(10):3442–6 (PubMed PMID: 20624773). 33. Ando M, Sasaki J, Hua H, Matsunaga A, Uchida K, Jou K, et al. A novel 18-amino acid deletion in apolipoprotein E associated with lipoprotein glomerulopathy. Kidney Int. 1999;56(4): 1317–23 (PubMed PMID: 10504484). 34. Mitani A, Ishigami M, Watase K, Minakata T, Yamamura T. A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy. J Atheroscler Thromb. 2011;18(6):531–5 (PubMed PMID: 21325775). 35. Tokura T, Itano S, Kobayashi S, Kuwabara A, Fujimoto S, Horike H, et al. A novel mutation ApoE2 Kurashiki (R158P) in a patient with lipoprotein glomerulopathy. J Atheroscler Thromb. 2011;18(6):536–41 (PubMed PMID: 21467726). 36. Hoffmann M, Scharnagl H, Panagiotou E, Banghard W, Wieland H, Marz W. Diminished LDL receptor and high heparin binding of apolipoprotein E2 Sendai associated with lipoprotein glomerulopathy. J Am Soc Nephrol. 2001;12(3):524–30 (PubMed PMID: 11181800). 37. Cheung CY, Chan AO, Chan YH, Lee KC, Chan GP, Lau GT, et al. A rare cause of nephrotic syndrome: lipoprotein glomerulopathy. Hong Kong Med J. 2009;15(1):57–60 (PubMed PMID: 19197098).
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REVIEW ARTICLE
WCN 2013 Satellite Symposium ‘‘Kidney and Lipids’’
Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia Akira Matsunaga • Takao Saito
Received: 4 October 2013 / Accepted: 23 October 2013 Ó Japanese Society of Nephrology 2014
Abstract Apolipoprotein E (ApoE) serves as a ligand for the low-density lipoprotein (LDL) receptor and cell surface receptors of the LDL receptor gene family. More than 10 different causative apoE mutations associated with lipoprotein glomerulopathy (LPG) have been reported. ApoE polymorphisms including three common phenotypes (E2, E3, E4), and a variety of rare mutations can affect blood cholesterol and triglyceride levels. The N-terminal domain of apoE is folded into a four-helix bundle of amphipathic a-helices, and contains the receptor-binding domain in which most apoE mutations that cause LPG or dominant mode of type III hyperlipoproteinemia (HL) are located. No single apoE mutation has been reported that causes both LPG and the dominant mode of type III HL. Keywords Apolipoprotein E Lipoprotein glomerulopathy Type III hyperlipoproteinemia Dominant mode Mutation
Introduction Lipoprotein glomerulopathy (LPG) is a rare renal disorder, characterized by the presence of lipoprotein thrombi in the glomeruli, an abnormal plasma lipoprotein profile that resembles type III hyperlipoproteinemia (HL), and a A. Matsunaga (&) Department of Laboratory Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan e-mail: [email protected] T. Saito General Medical Research Center, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
marked increase in serum apolipoprotein E (apoE) concentrations. Rare APOE mutations may contribute to the pathogenesis of the disease [1]. Since it was first described by Saito et al. in 1989 [2], the disease has been reported in approximately 150 patients, most of them in Japan, China, and other East Asian countries. Few cases have been reported in the United States or Europe. The purpose of this review was to understand the type of APOE mutations associated with LPG by comparing the differences in disease caused by a variety of APOE mutations with those of type III HL.
ApoE and polymorphisms ApoE is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types including the brain, kidney, adipocytes, and macrophages. It serves as a ligand for the receptor-mediated uptake of lipoproteins through the low-density lipoprotein (LDL) receptor, cell surface receptors of the LDL receptor gene family, and heparan sulfate proteoglycans. ApoE is normally present in the plasma at 5 mg/dl, and is one of the major apolipoproteins of cerebrospinal fluid and the central nervous system. It associates with chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL). ApoE knockout mice, which accumulate cholesterol-rich lipoproteins such as IDL and b-VLDL causing rapid atherosclerosis in the body, are used around the world as an animal model of arteriosclerosis [3]. The human APOE gene maps to chromosome 19 in a cluster with APOC1, APOC4, and APOC2 genes. ApoE is a glycoprotein with a molecular weight of 34 kDa consisting of 299 amino residues. Newly synthesized apoE is modified by O-glycosylation at Thr194, and this post-
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Clin Exp Nephrol
2/2 3/3 4/4 2/3 2/4 3/4
E4 E3 E2
Fig. 1 Isoelectric focusing and immunoblot analysis of the apoE phenotype. The six lanes show the apoE phenotypes E2/E2, E3/E3, E4/E4, E2/E3, E2/E4, and E3/E4, respectively
translational modification enables apoE to display several non-genetic isoforms contributed by differential sialylation [4]. APOE polymorphisms can lead to variations in blood cholesterol and triglyceride levels, and, typically, three different phenotypes (E2, E3, E4) have been determined by isoelectric focusing and the immunoblotting of delipidated neuraminidase-treated plasma (Fig. 1). ApoE3 is the predominant isoform. ApoE4 differs from apoE3 by an amino acid substitution at position 112 (C112R), while apoE2 has a substitution at position 158 (R158C). APOE genotyping is mainly performed by polymerase chain reaction-based restriction enzyme digestion and restriction fragment length polymorphism analysis on polyacrylamide gels [5]; the presence of the three most common APOE alleles (e2, e3, and e4) is determined by this method. ApoE4 is associated with increased cholesterol levels, thus enhancing the risk of heart disease [6]. In addition, E4/E4 individuals have a very high risk for developing Alzheimer’s disease [7]. Most patients with type III HL are homozygous for apoE2.
ApoE structure and dysbetalipoproteinemia ApoE contains two structural domains, an N-terminal and a C-terminal domain, each associated with a specific function. The N-terminal domain contains the lipoprotein receptor binding region and the C-terminal domain contains the major lipid binding elements. Most of the secondary structure, about 62 %, consists of amphipathic a-helices, while the remainder is made up of b-sheets
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(9 %), b-turns (11 %), and random structures (18 %). Receptor binding is important for the cellular uptake of lipoproteins, and is believed to occur because of the ionic interactions between the basic residues of apoE and the acidic residues (from aspartic and glutamic acids) of the lipid receptor. The strongest lipid binding occurs in the carboxyl terminal portion, between residues 244–272, and the five arginine and three lysine residues between residues 140–160 are essential for binding to the LDL receptor [8]. X-ray crystallography studies show that the N-terminal domain is folded into a four-helix bundle of amphipathic a-helices, containing the receptor binding region [9]. Helix 4 in apoE2 contains a critical salt bridge rearrangement that reduces the positive potential of the boxed LDL receptor binding side. Asp-154 changes its ionic interaction to Arg150 in apoE2 because of the Cys-158 substitution, pulling the side chain of Arg-150 out of the positive potential cloud and reducing its potential [10]. The apoE2 isoform shows \2 % of the normal receptor binding activity and is associated with a recessive mode of inheritance of type III HL. In this recessive form, the development of overt hyperlipidemia requires the inheritance of two alleles of APOE 2. The occurrence of the defective alleles is necessary but not usually sufficient to induce type III HL. Moreover, most apo E2/E2 subjects are either normolipidemic or even hypocholesterolemic. Thus, the development of the recessive form of overt hyperlipidemia involves other genetic, hormonal, or environmental influences that, in combination with the defective receptor binding of apoE, precipitate the development of hypertriglyceridemia and hypercholesterolemia. The secondary factors include diabetes, hypothyroidism, low-estrogen conditions, obesity, and age. Type III HL is characterized by xanthomas, and elevated plasma cholesterol and triglyceride levels, and is associated with premature atherosclerosis. Besides apoE2, which is associated with a recessive form of type III HL, a variety of rare naturally occurring APOE mutations have also been described that are associated with the dominant mode of inheritance of type III HL expressed at an early age (Fig. 2) [11–16]. The common feature of these dominant mutations is that they involve substitutions of basic residues at positions 136, 142, 145, 146, and 147. Eight of 14 mutations associated with the dominant mode of type III HL involve changes of arginine, and four lead to changes of lysine. Most of these amino acids are located within the receptor binding domain (residues 136–150) of apoE [10] or the first heparin binding domain (residues 142–147) of the molecule. Rare APOE mutations have also been identified which are associated either with LPG, or with the development of hypertriglyceridemia or hypercholesterolemia. With the exception of apoE5 (E3K), all mutations causing hypertriglyceridemia are located within the C-terminal domain of apoE—apoE1 Baden (R158C/R180C),
Clin Exp Nephrol Fig. 2 Schematic representation of apoE mutations with LPG (bottom) and dominant type III hyperlipoproteinemia (top). Mutations that cause both diseases are concentrated in the LDL receptor binding region (amino acids 136 to 150). However, the mutations that cause dominant type III hyperlipoproteinemia were not causative of lipoprotein glomerulopathy
ApoE2 (R145C)
ApoE2 (R136C) ApoE2 (R136S)
ApoE2 (R142L)
Dominant type III hyperlipoproteinemia
ApoE4 (G13K, R145K)
ApoE3 Leiden (partial duplication of 21 nucleotides 121-127) ApoE1 (G127D, R158C)
1
ApoE4 (G13K, R145K)
ApoE3 (C112R, R142C) ApoE2 (K146Q) ApoE1 Harrisburg (K146E) ApoE3’ Kochi (R145H) ApoE1 Hammersmith (K146N, R147W)
Receptor binding
ApoE1 (K164E)
Hinge region
136 150
Lipid binding 244 272
299
NH2
COOH
ApoE2 Kyoto (R25C)
Arg or Cys (112)
Arg61
Glu255
Arg or Cys (158)
ApoE2 Tsukuba (R114C)
ApoE2 Kanto (D151dupD) ApoE2 Las Vegas (A152D)
Lipoprotein glomerulopathy
ApoE2 Sendai (R145P)
ApoE1 (156-173del)
ApoE1 Tokyo/Maebashi (141-143del)
ApoE2 Osaka/Kurashiki (R158P)
ApoE2 Chicago (R147P) ApoE2 Okayama (R150G) ApoE2 Modena (R150C) ApoE2 Guangzhou (R150P)
apoE2 Dunedin (R228C), apoE2 (V236E), apoE3 (C112R/ R251G), and apoE7 Suita (E244R/E245R) [17–20].
Table 1 Differences between lipoprotein glomerulopathy and type III hyperlipoproteinemia Factor
APOE mutations and lipoprotein glomerulopathy LPG is a rare disorder, representing a unique entity of renal lipidosis, characterized by proteinuria, renal insufficiency, and disturbances in lipoprotein metabolism closely related to those observed in type III HL, with a marked increase in serum apoE concentrations. It also has the peculiar histopathologic characteristics of lipoprotein thrombi. Evidence demonstrating a clear association between common apoE2 and LPG are very limited [21]. Rare mutations in the APOE gene may contribute to the pathogenesis of the disease [1]. Notably, although LPG and type III HL phenotypes are similar, they are different diseases (Table 1). Several APOE mutations associated with LPG have been reported in Asian patient populations, the most common being apoE Sendai (R145P, a missense mutation substituting proline for arginine at position 145) [22], apoE Kyoto (R25C, a missense mutation substituting arginine for cysteine at position 25) [23], and apoE Tokyo/Maebashi (an in-frame deletion of Leu141 to Lys143del) (Table 2; Fig. 2) [24]. ApoE Sendai (R145P) is predominantly found in eastern Japan, and was recently identified in 13 LPG patients from nine unrelated families in this area [25]. It has not been reported in China. On the other hand, apoE Kyoto (R25C), first seen in Japanese patients, has been
Dyslipidemia Cutaneous xanthomas Atherosclerosis Renal involvement Genetics
Penetrance Distribution of patients
Disease Lipoprotein glomerulopathy
Type III hyperlipoproteinemia
Mild to moderate Absent
Severe Usually present
Absent Always present Heterozygosity for rare APOE mutations Incomplete Mainly in Japan and China
Usually present Rare Homozygosity of apoE2, heterozygosity for rare APOE mutations Incomplete Worldwide
reported in European, US, Japanese, and Chinese populations, while apoE Tokyo/Maebashi (141-143del) was identified in both Japanese and Chinese individuals. Recently, apoE Kyoto (R25C) was found in 35 patients from 31 unrelated Chinese Han families with LPG, and 28 asymptomatic relatives [26]. Several different APOE mutations, including apoE Tsukuba (R114C), apoE Chicago (R147P), apoE Okayama (R150G), apoE Modena (R150G), apoE Guangzhou (R150P), apoE Las Vegas (A152D), apoE Osaka/Kurashiki (R158P), and apoE1(156-173del) have also been discovered in patients with LPG (Table 2; Fig. 2) [27–35]. All these studies suggested that LPG may be a dominant
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Clin Exp Nephrol Table 2 APOE mutations found in lipoprotein glomerulopathy Protein sequence changea
Mutation
Genomic changeb
ApoE phenotypes
References
apoE Kyoto (R25C)
p.R43C
c.61G[T
E2/E4, E2/E3
[23]
apoE Tsukuba (R114C)
p.R132C
c.394C[T
E2/E3
[27]
apoE Tokyo/Maebashi (141-143del/142-144del)
p.159_161delLRK/
c.475_483del9/
E1/E3
[24]
p.160_162delRKL
c.480_488del9
apoE Sendai (R145P)
p.R163P
c.488G[C
E2/E3, E2/E4
[22]
apoE Chicago (R147P)
p.R165P
c.494G[C
E2/E3c
[28]
apoE Okayama (R150G)
p.R168G
c.502C[G
E2/E3
[29]
apoE Modena (R150C)d
p.R168C
c.502C[T
E1/E2c
[30]
apoE Guangzhou (R150P)
p.R168P
c.503G[C
E2/E3c
[31]
apoE Kanto (D151dupD)
e
p.D169dupD
c.508-510dupGAT
E2/E3
apoE Las Vegas (A152D) apoE1 (156-173del)
p.A170D p.174_191del
c.509C[A c.520_573del
E2/E3c E1/E3
[32] [33]
apoE Osaka/Kurashiki (R158P)
p.R176P
c.527G[C
E2/E3
[34, 35]
apoE Hong Kong (D230Y)f
p.D248Y
c.742G[T
E2/E4 or E3/E3c
[37]
a
p. represents protein sequence, and the translation initiator Methionine is numbered ?1
b
c. represents coding DNA sequence, and nucleotide 1 is the A of the ATG-translation initiation codon
c
Speculative phenotype
d
Homozygous E2/E2 and heterozygosis for apoE Modena was documented
e
Unpublished case
f
DNA analysis identified both apoE Kyoto and apoE Hong Kong
inherited disease with incomplete penetrance. Eight of 12 mutations with LPG were changes of arginine, and most were located in the LDL receptor binding region, suggesting that binding of the mutated apoE to the LDL receptor may be affected because of the altered threedimensional structure of apoE. ApoE Sendai (R145P) and apoE Kyoto (R25C) have also been shown to be defective in binding to the LDL receptor [23, 36]. As shown in Fig. 2, most APOE mutations associated with the dominant mode of type III HL are located between residues 136 and 146, compared with most LPG-associated APOE mutations between residues 141 and 158. No mutation related to LPG or the dominant mode of type III HL has been identified in the C-terminal domain. Missense mutations substituting histidine, lysine, or cysteine for arginine at residue 145 cause the dominant mode of type III HL, and a mutation substituting proline at residue 145 (apoE Sendai) causes LPG. Mutations substituting glycine, cysteine, or proline for arginine at residue 150 cause LPG, while mutations substituting glutamine, glutamic acid, or asparagine for arginine at residue 145 cause the dominant mode of type III HL. Proline is established as a potent breaker of both a-helical and b-sheet structures in soluble proteins, and missense mutations substituting proline for arginine at positions 145, 147, 150 or 158 induce LPG. No single APOE mutation has been found to cause both LPG and the dominant mode of type III HL.
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Conflict of interest interest exists.
The authors have declared that no conflict of
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