Significance of a Novel Apolipoprotein E Variant, ApoE Osaka/Kurashiki, in Lipoprotein Glomerulopathy
Open accessAbstract
Lipoprotein glomerulopathy (LPG) is a unique kidney disease characterized by lipoprotein thrombi in the glomerulus. Type III hyperlipoproteinemia with a high apolipoprotein E (apoE) level in serum is a distinctive feature in the lipoprotein profile. Approximately 100 cases of LPG have been reported in the world since we published the first case in the American Journal of Kidney Diseases in 1989, and the characteristics mentioned above are common to almost all LPG cases. Accordingly, it has been suspected that abnormal lipoproteins induced by apoE variants play a pivotal role in the formation of lipoprotein thrombi of LPG. Thirteen different apoE variants were detected in LPG cases since we discovered apoE Sendai (Arg145Pro) in 1997. These LPG-related apoE variants are mainly caused by point mutations of amino acid residues around the LDL-receptor binding domain, and constitute isoforms with apoE2 or E1 allele. In this issue, cases of LPG with the same novel variant, apoE2 (Arg158Pro), are published independently, and the variants are called apoE Osaka and apoE Kurashiki, respectively . Patients in both reports were not relatives and the distance between their homes was 130 km, although they might have had remote ancestors in common. ApoE is an arginine-rich protein and the substitution of cysteine for arginine at position 158 is recognized as a common apoE2 mutation causing familial type III hyperlipoproteinemia; however, the substitution of proline for arginine at the same position is not known so far. On the other hand, the substitution of proline for arginine was the first apoE mutation in LPG, called apoE Sendai (Arg145Pro), which comprises the majority of apoE variants related to LPG. Moreover, apoE Chicago (Arg147Pro) and apoE Guangzhou (Arg150Pro) have been reported in the United States and China, respectively. Proline acts as a structural disrupter in the middle of the alpha helix, and is commonly found as the first residue of the alpha helix or in turns in an amino acid arrangement . Accordingly, proline is not in or around the LDL-receptor binding domain of apoE which forms a continuous alpha helix. Once the substitution of proline occurs in this area, however, apoE may seriously change its structure, aggregate lipoproteins and induce intraglomerular lipoprotein thrombi of LPG. It is of interest that the substitution of proline associated with LPG was found at position 158, where the common apoE2 mutant inducing familial type III hyperlipoproteinemia possesses cysteine. In this point, we recognize that both reports published in this issue 6) are very valuable and propose that the novel variant be called apoE Osaka/Kurashiki. In LPG, apoE variants having 3 amino acid deletions were reported independently as apoE Tokyo (del 141-143) and apoE Maebashi (del 142-144). But both deletions were recognized to be the same because the amino acid arrangement was repeated between 141 and 146. Now, this variant is generally called apoE Tokyo/Maebashi and is found not only in Japan but also in China. The discovery of apoE Osaka/ Kurashiki will widen the scope of the study of LPG.
AI snapshot
Written from the paper’s full text.
TL;DR
This editorial argues that two independently reported novel apolipoprotein E variants in lipoprotein glomerulopathy (LPG), apoE Osaka and apoE Kurashiki, are in fact the same variant, apoE2 (Arg158Pro), and proposes the unified name apoE Osaka/Kurashiki. It places this finding within the broader pattern of proline-substitution apoE variants associated with LPG.
Key findings
- Two reports published in the same issue describe unrelated LPG patients carrying the same novel variant, apoE2 (Arg158Pro); the patients were not relatives and lived 130 km apart, though the authors note they "might have had remote ancestors in common."
- The substitution of proline for arginine at position 158 is distinct from the common apoE2 mutation (cysteine for arginine at 158) that causes familial type III hyperlipoproteinemia; a proline substitution at this position "is not known so far."
- Proline acts as a structural disrupter in the middle of an alpha helix and is normally found at helix starts or turns, not in or around the LDL-receptor binding domain; the authors propose that such a substitution may seriously alter apoE structure, aggregate lipoproteins, and induce intraglomerular lipoprotein thrombi.
- Approximately 100 LPG cases have been reported worldwide since the first case in 1989, and 13 different apoE variants have been detected in LPG cases since apoE Sendai (Arg145Pro) was discovered in 1997.
Methods
- Narrative editorial/commentary synthesizing the existing LPG and apoE-variant literature; no new primary data, patients, or experiments are presented.
- Draws on the two accompanying reports in the same issue (Mitani et al., apoE Osaka; Tokura et al., apoE2 Kurashiki) plus prior case reports of apoE Sendai, apoE Chicago, apoE Guangzhou, apoE Tokyo, and apoE Maebashi.
- The naming proposal rests on analogy to the precedent in which apoE Tokyo (del 141-143) and apoE Maebashi (del 142-144) were recognized as the same variant because the amino acid arrangement repeats between positions 141 and 146, and are now generally called apoE Tokyo/Maebashi.
Limitations
- Not stated in the paper: the editorial does not list limitations, and it presents no structural or functional data to test the proposed mechanism by which proline substitution at position 158 causes lipoprotein thrombi.
- Evident from the text: the conclusion that apoE Osaka and apoE Kurashiki are the same variant is inferred from the two independent reports rather than from direct comparative biochemical or genetic analysis; the authors themselves hedge on shared ancestry ("might have had remote ancestors in common").
- Evident from the text: the mechanistic claim that proline substitution "may seriously change its structure, aggregate lipoproteins and induce intraglomerular lipoprotein thrombi" is framed as a hypothesis, not a demonstrated result.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
8 of 22 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Two independent reports in this issue describe LPG cases with the same novel apolipoprotein E variant, apoE2 (Arg158Pro).
“In this issue, cases of LPG with the same novel variant, apoE2 (Arg158Pro), are published independently”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [5] source
The Discussion (page unavailable) reports an LPG case with the novel Arg158Pro variant, which the paper names apoE Osaka. It does not document a second independent report in the same issue, and it distinguishes apoE Osaka from apoE2, which it identifies as Arg158Cys. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [6] source
The Results (page unavailable) identify this paper as a report of an LPG case with the novel apoE2 (Arg158Pro) variant. Our copy does not identify a second independent report of the same variant or establish that both appeared in the same issue. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisenone given
LPG-related apolipoprotein E variants are mainly caused by point mutations of amino acid residues around the LDL-receptor binding domain.
“These LPG-related apoE variants are mainly caused by point mutations of amino acid residues around the LDL-receptor binding domain”
Quote in the paperNot a substantial claim - Premisecitation
The substitution of proline for arginine was the first apolipoprotein E mutation in LPG, called apoE Sendai (Arg145Pro).
“the substitution of proline for arginine was the first apoE mutation in LPG, called apoE Sendai (Arg145Pro) 4)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] 4) 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, Sasaki J: Apolipoprotein E Sendai (Arginine 145 → Proline): A new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 source
- Premisecitation
Type III hyperlipoproteinemia with a high serum apolipoprotein E level is a distinctive feature of the lipoprotein profile in lipoprotein glomerulopathy.
“Type Ⅲ hyperlipoproteinemia with a high apolipoprotein E (apoE) level in serum is a distinctive feature in the lipoprotein profile 2) .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] 2) Oikawa S, Suzuki N, Sakuma E, Saito T, Namai K, Kotake H, Fujii Y, Toyota T: Abnormal lipoprotein and apolipoprotein pattern in lipoprotein glomerulopathy. Am J Kidney Dis, 1991; 18: 553-558 source
- Premisecitation
Thirteen different apolipoprotein E variants have been detected in lipoprotein glomerulopathy cases since the discovery of apoE Sendai (Arg145Pro) in 1997.
“Thirteen different apoE variants were detected in LPG cases since we discovered apoE Sendai (Arg145Pro) in 1997 4) .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] 4) 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, Sasaki J: Apolipoprotein E Sendai (Arginine 145 → Proline): A new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 source
- Premisecitation
ApoE Sendai comprises the majority of apolipoprotein E variants related to LPG.
“which comprises the majority of apoE variants related to LPG.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] 4) 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, Sasaki J: Apolipoprotein E Sendai (Arginine 145 → Proline): A new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 source
- Interpretationreasoning
The apoE Tokyo and apoE Maebashi deletions are the same because the amino acid arrangement was repeated between 141 and 146.
“But both deletions were recognized to be the same because the amino acid arrangement was repeated between 141 and 146.”
Quote in the paperNot a substantial claim - Premisecitation
Proline acts as a structural disrupter in the middle of the alpha helix.
“Proline acts as a structural disrupter in the middle of the alpha helix”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] source
- cites [4] 4) 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, Sasaki J: Apolipoprotein E Sendai (Arginine 145 → Proline): A new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 source
- Premisereasoning
LPG-related apolipoprotein E variants constitute isoforms with apoE2 or E1 allele.
“and constitute isoforms with apoE2 or E1 allele.”
Quote in the paperNot a substantial claim - Premisecitation
In LPG, apolipoprotein E variants having 3 amino acid deletions were reported independently as apoE Tokyo (del 141-143) and apoE Maebashi (del 142-144).
“In LPG, apoE variants having 3 amino acid deletions were reported independently as apoE Tokyo (del 141-143) 10) and apoE Maebashi (del 142-144) 11) .”
Quote in the paperNot a substantial claim0 of 2 sources checked
- Classified as probably not a substantial claim. 9
- May combine two claims. 3
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe variants in the two reports are called apoE Osaka and apoE Kurashiki, respectively.
“and the variants are called apoE Osaka and apoE Kurashiki, respectively 5,6) .”
Quote in the paperNot a substantial claim2 of 2 sources checkedMay combine two claims.
PremisecitationThe patients in the two reports were not relatives and lived 130 km apart.
“Patients in both reports were not relatives and the distance between their homes was 130 km”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [5] source
The Introduction describes a patient from Osaka, and the Discussion describes that patient's mutation, but neither passage compares patients from two reports. Searches for relatives, family relationships, and a 130 km distance found no passage establishing either part of the claim. Page numbers were unavailable in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [6] source
The Case Presentation describes one patient and says he had no family history of kidney or hereditary disease. Neither it nor the Discussion states whether patients in two reports were related or gives a 130 km distance between their homes. Searches for those details found no supporting passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenApoE Tokyo/Maebashi is found not only in Japan but also in China.
“and is found not only in Japan but also in China.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApolipoprotein E is an arginine-rich protein.
“ApoE is an arginine-rich protein”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Mahley, R. W., Innerarity, T. L., R, 1984 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE Guangzhou (Arg150Pro) has been reported in China.
“apoE Chicago (Arg147Pro) 8) and apoE Guangzhou (Arg150Pro) 9) have been reported in the United States and China, respectively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] 9) Luo B, Huang F, Liu Q, Li X, Chen W, Zhou SF, Yu X: Identification of apolipoprotein E Guangzhou (arginine 150 proline), a new variant associated with lipoprotein glomerulopathy. Am J Nephrol, 2008; 28: 347-353 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE Chicago (Arg147Pro) has been reported in the United States.
“apoE Chicago (Arg147Pro) 8) and apoE Guangzhou (Arg150Pro) 9) have been reported in the United States and China, respectively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] source
May combine two claims.
InterpretationreasoningProline is not in or around the LDL-receptor binding domain of apolipoprotein E, which forms a continuous alpha helix.
“Accordingly, proline is not in or around the LDL-receptor binding domain of apoE which forms a continuous alpha helix.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe substitution of cysteine for arginine at position 158 is a common apoE2 mutation causing familial type III hyperlipoproteinemia.
“the substitution of cysteine for arginine at position 158 is recognized as a common apoE2 mutation causing familial type Ⅲ hyperlipoproteinemia 7)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Mahley, R. W., Innerarity, T. L., R, 1984 source
Classified as probably not a substantial claim.
PremisecitationProline is commonly found as the first residue of the alpha helix or in turns in an amino acid arrangement.
“and is commonly found as the first residue of the alpha helix or in turns in an amino acid arrangement 1, 4)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] source
- cites [4] 4) 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, Sasaki J: Apolipoprotein E Sendai (Arginine 145 → Proline): A new variant associated with lipoprotein glomerulopathy. J Am Soc Nephrol, 1997; 8: 820-823 source
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningThe discovery of apoE Osaka/Kurashiki will widen the scope of the study of LPG.
“The discovery of apoE Osaka/ Kurashiki will widen the scope of the study of LPG.”
Quote in the paperNot a substantial claim- Rests on an assumption: Abnormal lipoproteins induced by apolipoprotein E variants play a pivotal role in the formation of lipoprotein thrombi of LPG.
May combine two claims.
InterpretationreasoningIf a proline substitution occurs in the LDL-receptor binding domain of apolipoprotein E, apoE may seriously change its structure, aggregate lipoproteins, and induce intraglomerular lipoprotein thrombi of LPG.
“Once the substitution of proline occurs in this area, however, apoE may seriously change its structure, aggregate lipoproteins and induce intraglomerular lipoprotein thrombi of LPG.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisereasoningThis variant is generally called apoE Tokyo/Maebashi.
“Now, this variant is generally called apoE Tokyo/Maebashi”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The substitution of proline for arginine at position 158 was not previously known.
“however, the substitution of proline for arginine at the same position is not known so far.”
The paper relies on this without support.
Abnormal lipoproteins induced by apolipoprotein E variants play a pivotal role in the formation of lipoprotein thrombi of LPG.
“Accordingly, it has been suspected that abnormal lipoproteins induced by apoE variants play a pivotal role in the formation of lipoprotein thrombi of LPG.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
APOE-Osaka/Kurashiki was reported for the first time outside of Japan.
“For the first time we report APOE‐Osaka/Kurashiki outside of Japan (Saito & Matsunaga, 2011).”
From Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by <i>APOE</i> mutations (2020) · cites this paper as Saito & Matsunaga, 2011
Cites
Plasma lipoproteins: apolipoprotein structure and function.
Mahley, R. W., Innerarity, T. L., Rall, S. C., & Weisgraber, K. H. (1984) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)34443-6 · Cited by 1,155 · see citing works
Lipoprotein Glomerulopathy: Glomerular Lipoprotein Thrombi in a Patient With Hyperlipoproteinemia
Saito, T., Sato, H., Kudo, K.-I., Oikawa, S.-I., Shibata, T., Hara, Y., Yoshinaga, K., & Sakaguchi, H. (1989) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(89)80134-9 · Cited by 148 · see citing works
Self-citationOikawa, S., Matsunaga, A., Saito, T., Sato, H., Seki, T., Hoshi, K., Hayasaka, K., Kotake, H., Midorikawa, H., Sekikawa, A., et al. (1997) · Journal of the American Society of Nephrology · doi:10.1681/asn.v85820 · Cited by 103 · see citing works
Self-citationImpact of Lipoprotein Glomerulopathy on the Relationship Between Lipids and Renal Diseases
Saito, T., Matsunaga, A., & Oikawa, S. (2006) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2005.10.017 · Cited by 96 · see citing works
Self-citationAbnormal Lipoprotein and Apolipoprotein Pattern in Lipoprotein Glomerulopathy
Oikawa, S., Suzuki, N., Sakuma, E., Saito, T., Namai, K., Kotake, H., Fujii, Y., & Toyota, T. (1991) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(12)80649-4 · Cited by 60 · see citing works
Self-citationKonishi, K., Saruta, T., Kuramochi, S., Oikawa, S., Saito, T., Han, H., Matsunaga, A., & Sasaki, J. (1999) · Nephron · doi:10.1159/000045513 · Cited by 54 · see citing works
Self-citationLipoprotein Glomerulopathy: A New Apolipoprotein E Mutation With Enhanced Glomerular Binding
Sam, R., Wu, H., Yue, L., Mazzone, T., Schwartz, M. M., Arruda, J. A. L., Dunea, G., & Singh, A. K. (2006) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2005.12.031 · Cited by 53 · see citing works
A new variant of apolipoprotein E (apo E Maebashi) in lipoprotein glomerulopathy
Ogawa, T., Maruyama, K., Hattori, H., Arai, H., Kondoh, I., Egashira, T., Watanabe, T., Kobayashi, Y., & Morikawa, A. (2000) · Pediatric Nephrology · doi:10.1007/s004670050032 · Cited by 37 · see citing works
Luo, B., Huang, F., Liu, Q., Li, X., Chen, W., Zhou, S.-F., & Yu, X. (2008) · American Journal of Nephrology · doi:10.1159/000111828 · Cited by 36 · see citing works
A Novel Mutation ApoE2 Kurashiki (R158P) in a Patient with Lipoprotein Glomerulopathy
Tokura, T., Itano, S., Kobayashi, S., Kuwabara, A., Fujimoto, S., Horike, H., Satoh, M., Komai, N., Tomita, N., Matsunaga, A., et al. (2011) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.8102 · Cited by 28 · see citing works
Self-citationMitani, A., Ishigami, M., Watase, K., Minakata, T., & Yamamura, T. (2011) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.7377 · Cited by 24 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
APOE gene variants in primary dyslipidemia
Khalil, Y. A., Rabès, J.-P., Boileau, C., & Varret, M. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.007 · Cited by 170 · see citing works
Update on the molecular biology of dyslipidemias
Ramasamy, I. (2015) · Clinica Chimica Acta · doi:10.1016/j.cca.2015.10.033 · Cited by 126 · see citing works
Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by <i>APOE</i> mutations
Yang, M., Weng, Q., Pan, X., Hussain, H. M. J., Yu, S., Xu, J., Yu, X., Liu, Y., Jin, Y., Zhang, C., et al. (2020) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.1281 · Cited by 15 · see citing works
Cambruzzi, E., & Pêgas, K. L. (2019) · Brazilian Journal of Nephrology · doi:10.1590/2175-8239-jbn-2018-0148 · Cited by 14 · see citing works
Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice
Wu, H., Yang, J., Liu, Y.-Q., Lei, S., Yang, M., Yang, Z., Yang, Y., & Hu, Z. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02765-x · Cited by 10 · see citing works
Wu, H., Yang, J., Liu, Y.-Q., Lei, S., Yang, M., Yang, Z., Yang, Y., & Hu, Z. (2021) · Figshare · doi:10.6084/m9.figshare.14167912
Wu, H., Yang, J., Liu, Y.-Q., Lei, S., Yang, M., Yang, Z., Yang, Y., & Hu, Z. (2021) · Figshare · doi:10.6084/m9.figshare.14167909
- Authors
- Saito, T., & Matsunaga, A.
- Affiliations
- Fukuoka University (JP)
- Venue
- Journal of Atherosclerosis and Thrombosis
- Publisher
- Japan Atherosclerosis Society
- Published
- 2011
- Volume
- 18
- Issue
- 6
- Pages
- 542-543
- ISSN
- 1340-3478 (ISSN-L)
- 1880-3873
- OpenAlex
- W1989567790
- Semantic Scholar
- a246f59fee375b3dac78a2fc26a5a580c69b3e5e
- Cited by
- 7
- References
- 11
- Citations by year
- 2021: 4 · 2020: 1 · 2018: 1 · 2015: 1
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- Journal of Atherosclerosis and Thrombosis (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, lipoprotein glomerulopathy, genetic variants, lipoprotein metabolism, glomerular disease
- MeSH terms
- Apolipoproteins E, Humans, Kidney Diseases, Kidney Glomerulus, Lipoproteins, Male, Mutation, Dyslipidemias, Apolipoprotein E2
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
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