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Cited by 28Lipid metabolism and disordersLipoproteins and Cardiovascular HealthCholesterol and Lipid Metabolism

Dominant expression of type III hyperlipoproteinemia. Pathophysiological insights derived from the structural and kinetic characteristics of ApoE-1 (Lys146-->Glu).

Open access
Mann, W A, Lohse, P, Gregg, R E, Ronan, R, Hoeg, J M, Zech, L A, Brewer, H B·1995·Journal of Clinical Investigation
DOI 10.1172/jci118096PMC PMC185299
Open this paper in CoChat — free accountOpen PDF

Abstract

Type III hyperlipoproteinemia is characterized by delayed chylomicron and VLDL remnant catabolism and is associated with homozygosity for the apoE-2 allele. We have identified a kindred in which heterozygosity for an apoE mutant, apoE-1 (Lys146-->Glu), is dominantly associated with the expression of type III hyperlipoproteinemia. DNA sequence analysis of the mutant apoE gene revealed a single-point mutation that resulted in the substitution of glutamic acid (GAG) for lysine (AAG) at residue 146 in the proposed receptor-binding domain of apoE. The pathophysiological effect of this mutation was investigated in vivo by kinetic studies in the patient and six normal subjects, and in vitro by binding studies of apoE-1 (Lys146-->Glu) to LDL receptors on human fibroblasts and to heparin. The kinetic studies revealed that apoE-1 (Lys146-->Glu) was catabolized significantly slower than apoE-3 in normals (P < 0.005). In the proband, the plasma residence times of both apoEs were substantially longer and the production rate of total apoE was about two times higher than in the control subjects. ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. The affinity of apoE-1 (Lys146-->Glu) to heparin was also markedly reduced compared with both apoE-2 (Arg158-->Cys) and apoE-3. These abnormal in vitro binding characteristics and the altered in vivo metabolism of apoE-1 (Lys146-->Glu) are proposed to result in the functional dominance of this mutation in the affected kindred.

AI snapshot

Written from the paper’s full text.

TL;DR

A kindred with dominantly expressed type III hyperlipoproteinemia was found to carry a heterozygous apoE-1 (Lys146→Glu) mutation. The mutant apoE shows markedly defective LDL-receptor and heparin binding and prolonged in vivo catabolism, with increased production, explaining its dominant pathophysiological effect.

Key findings

  • DNA sequencing identified a single G-to-A exchange at position 254 in exon 4 of the apoE gene, causing Lys (AAG) to Glu (GAG) at residue 146; the proband was heterozygous for apoE-1 (Lys146→Glu)/apoE-3.
  • In six normal apoE-3/3 controls, apoE-1 (Lys146→Glu) was catabolized significantly slower than apoE-3 (residence time 0.91±0.17 d vs 0.66±0.07 d, P<0.005). In the proband, residence times were 3.76 d for apoE-1 and 2.32 d for apoE-3, and total apoE production was about twofold higher than controls at 6.2 mg/kg/d.
  • ApoE-1 (Lys146→Glu) displaced LDL from normal human fibroblast LDL receptors at 7.7±0.7% of apoE-3 activity, similar to apoE-2 (8.4±1.0%). Heparin binding under nondenaturing conditions was reduced to 10% of apoE-3 for apoE-1 and 60% for apoE-2; denaturation restored apoE-2 binding but not apoE-1.
  • The authors propose dominant expression results from overexpression of the mutant allele, impaired LDL-receptor binding, and slow plasma removal of particles containing both mutant and normal apoE, with defective heparin/proteoglycan binding possibly contributing.

Methods

  • The proband with type III hyperlipoproteinemia and six healthy young apoE-3/3 controls (aged 19–23) were studied; genomic DNA was amplified by PCR, subcloned, and sequenced by dideoxynucleotide chain termination.
  • In vivo kinetics used simultaneous injection of 125I-apoE-1 (Lys146→Glu) and 131I-apoE-3, plasma sampling through day 7, and SAAM 29 curve fitting to calculate residence time, fractional catabolic rate, and production rate; groups were compared by Student’s t test.
  • In vitro studies measured apoE liposome competition with 125I-LDL for binding to normal human fibroblasts and apoE binding to heparin-Sepharose under nondenaturing and 5 M urea denaturing conditions.

Limitations

  • Stated: direct measurements of transcriptional or secretional levels could not be done because a liver biopsy would have been required.
  • Stated: the physiological relevance of in vivo apoE binding to heparin is unknown.
  • Evident: the kinetic and clinical conclusions rest on a single proband/kindred plus six young normal controls, and the in vitro binding and in vivo turnover associations cannot by themselves establish causality for the dominant phenotype.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci118096

Cites

58 of 58 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 34 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Under nondenaturing conditions, the amount of apoE-1 (Lys146->Glu) and apoE-2 bound to heparin-Sepharose was decreased to 10% and 60%, respectively, compared with apoE-3.

    “Under nondenaturing conditions, the amount of apoE-1 (Lys '-+Glu) and apoE-2 bound to heparin-Sepharose was decreased to 10 and 60%, respectively, compared with the amount of apoE-3 bound (Fig. 2 A).”
    Quote in the paperSubstantial claim
  • Findingown data

    In the proband, plasma residence times of both apoE-1 (Lys146->Glu) and apoE-3 were substantially longer than in control subjects.

    “In the proband, the plasma residence times of both apoEs were substantially longer”
    Quote in the paperSubstantial claim
  • Findingown data

    In the proband, the majority of apoE-1 (Lys146->Glu) and apoE-3 accumulated in the VLDL subfraction, in contrast to controls.

    “However, in contrast to the controls, the majority of apoE- 1 (Lys lteGlu) and apoE-3 accumulated in the VLDL subfraction of the proband.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    ApoE-1 predominates in plasma over normal apoE-3 at a ratio of approximately 3:1 in the proband.

    “explains the predominance in plasma of apoE-I(Lys 1-+Glu) over normal apoE-3 at a ratio of approximately 3:1”
    Quote in the paperSubstantial claim
  • Findingown data

    Affinity of apoE-2 for heparin was 59% of normal.

    “whereas the affinity of apoE-2 was Nonnal ApoE-3 I yYYYYYyyyy yyylyyy ACACAAAAAAA^A^^8188 HSPG LR HSPG LR ApoE-1 (Lys14-GIu) HSPG LR HSP LR 59% of normal.”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 2
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 8

  • The quote only partly states this claim.

    Findingown data

    Both apoE-1 (Lys146->Glu) and apoE-2 were comparably defective in displacing LDL from receptors on normal human fibroblasts (apoE-1: 7.7±0.8%; apoE-2: 8.5±1.0%).

    “ApoE-2 and apoE-1 (Lys '-+Glu) were both shown to possess 8% of normal receptor-binding activity in an in vitro competition assay using apoE liposomes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unfolding under denaturing conditions normalized heparin binding of apoE-2, while apoE-1 remained defective.

    “Unfolding of the protein under denaturing con- ditions resulted in a normalization of the heparin binding of apoE-2, while apoE-I(Lys”
    • Also stated in: § Discussion · plain
      “remained defective.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The mutant apoE-1 has a twofold increased production rate and secretion compared with normal apoE-3.

    “The espe- cially slow removal from circulation of the mutant apoE and its twofold increased production rate and secretion, compared with the normal counterpart”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The proband from the Harrisburg kindred catabolized both apoE-1 and apoE-3 much slower than normal controls, resulting in accumulation in plasma of particles containing both mutant and normal apoE.

    “This would explain why the proband from the Harrisburg kindred catabolized both apoE-1 (Lys '46-Glu) and apoE-3 much slower than did the normal controls, resulting in the accumulation in plasma of particles containing both mutant and normal apoE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The mean residence time for apoE-3 in normal subjects was 0.66±0.07 d, with production rate 3.09±0.75 mg/kg x d.

    “The mean RT for apo E-3 in the normal subjects was 0.66±0.07d, with the production rate at 3.09±0.75mg/ kg x d, which agrees with previous turnover studies of apoE- 3 (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Findingown data

    Denaturation with 5 M urea restored the ability of apoE-2 to bind to heparin-Sepharose, while apoE-1 (Lys146->Glu) remained defective.

    “Denaturation of the apoEs with 5 M urea restored the ability of apoE-2 to bind to heparin-Sepharose, while apoE-I(Lys 46--Glu) remained de- fective (Fig. 2 B).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The proband had palmar xanthomas, tuberous xanthomas on his extremities, and xanthelasma.

    “Physical findings include palmar xanthomas, tuberous xanthomas on his extremit- ies, and xanthelasma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband's plasma cholesterol was 404 mg/dl with VLDL cholesterol 284 mg/dl.

    “At the time of the study, he was without lipidlowering medications, and his plasma cholesterol value was 404 mg/dl with a VLDL cholesterol of 284 mg/dl (Table I).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The proband is heterozygous for the apoE-1 (Lys146->Glu) allele, with the other allele encoding normal apoE-3.

    “The other allele was found to be normal, thus establishing that the patient is a heterozygote for the I-I(Lys '--.Glu) allele.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Study design and conductnone given

    The exact amount of apoE injected was estimated to be <1% of total pool size and thus did not significantly affect steady state conditions.

    “The exact amount of apoE injected was not calculated but was estimated to be < 1% of the total pool size and thus did not significantly affect steady state conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    The increased pool size of lipoproteins with low receptor affinity in the proband is explained by slow removal and increased production of mutant apoE.

    “and the increased pool size of lipoproteins with low receptor affinity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The latter mutant demonstrates the importance not only of the position of the mutated residue, but also of the charge of the newly introduced amino acid on LDL receptor-binding activity.

    “The latter mutant demonstrates the importance not only of the posi- tion of the mutated residue, but also of the charge of the newly introduced amino acid on LDL receptor-binding activity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    ApoE liposomes were used in in vitro competition assays to exclude apoB-LDL receptor interactions.

    “ApoE liposomes were used for these in vitro competition assays to exclude apoB-LDL receptor interactions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The increased apoE levels in the proband were due to both a decreased fractional catabolic rate and an increased production rate.

    “The increased apoE levels in the proband were therefore due to both a decreased fractional catabolic rate and an increased production rate.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    Direct measurements of transcriptional or secretional levels could not be done because a liver biopsy would have been required.

    “However, direct measurements of transcriptional or secretional levels could not be done because a liver biopsy would have been required.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Type III HLP is characterized by impaired chylomicron and VLDL remnant catabolism and accumulation of cholesterol- and apoE-enriched remnant particles.

    “Structural defects of the apoE may result in the expression of type III hyperlipoproteinemia (HLP),' which is characterized by an impaired chylomicron and VLDL remnant catabolism and the accumulation of cholesterol and apoE-enriched remnant particles (for reviews see references 6-8).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationcitation

    ApoE-1 (Lys146->Glu) is the most binding-defective naturally occurring apoE mutant described, with the exception of apoE-2(Arg158->Cys), which has a receptor-binding activity as low as 1%.

    “With the exception of apoE-2(Arg '58--Cys), which has a receptor-binding activity as low as 1% (10), apoE-l(Lys'40_ Glu) is the most binding-defective naturally occurring apoE mutant described.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    The defect of apoE-1 appears more severe because it results in dominant manifestation of disease as opposed to the recessive mode observed for apoE-2.

    “However, the defect of apoE-1 appears more severe, because it results in dominant manifestation of disease as opposed to the recessive mode observed for apoE-2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Binding of apoE to heparan sulfate proteoglycans could bring triglyceride- and apoE-rich particles close to lipolytic enzymes, enhancing hydrolysis of triglycerides and cellular binding/uptake.

    “In addition, binding of apoE-to heparan sulfate proteoglycans could bring triglycer- ide-and apoE-rich particles into close spatial relationship with lipolytic enzymes (hepatic lipase, reference 59, lipoprotein li- pase: reference 60), thereby enhancing hydrolysis of triglycer- ides as well as cellular binding and uptake of these lipoproteins.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [60]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    ApoE-1 (Lys146->Glu) not only has an impaired in vivo metabolism but also interferes with the catabolism of apoE-3, leading to a greatly prolonged residence time of the normal E isoprotein in the patient.

    “These results demonstrate that apoE-I (Lys '-+Glu) not only has an impaired in vivo metabolism but also interferes with the catabolism of apoE-3, thus leading to a greatly pro- longed residence time of the normal E isoprotein in the patient.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The results agree with previously performed amino acid analyses of the mutant apoE.

    “These results agree with previously performed amino acid analyses of the mutant apoE (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    There are two heparin-binding sites in the apoE molecule, one contained within the region implicated in LDL receptor binding (amino acids 135-150).

    “There are two heparin-binding sites in the apoE molecule (48, 49), and one is contained within the region of the molecule implicated in LDL receptor binding (amino acids 135-150).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [49]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A second family with type III HLP due to the identical mutation has been identified in Japan.

    “Since our initial description of this kindred, a second family with type III HLP due to the identical mutation has been identified in Japan(25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Homozygosity for the apoE-2 allele is permissive for, but in 95% of cases not associated with, development of type III HLP.

    “However, homozygosity for the 1-2 allele is permissive for, but in 95% of the cases not associated with, the development of type III HLP, and other hyperlipidemic factors appear to contribute to the manifestation of this disease (11,12).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study protocol was approved by the Institute Review Board of the National Heart, Lung, and Blood Institute, and subjects gave informed consent.

    “All normal volunteers and the proband from the Harrisburg kindred were studied as in-patients at the Clinical Center of the National Institutes of Health and gave informed consent to the study protocol, which was approved by the Institute Review Board of the National Heart, Lung, and Blood Institute.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The replacement of residue 142 arginine by cysteine in apoE-3 results in weaker affinity for heparin as measured by salt gradient elution.

    “The replace- ment of residue 142, arginine, by cysteine in apoE-3 (Cys”
    • Also stated in: § Discussion · boosted
      “has already been shown to result in a weaker affinity for heparin as measured by salt gradient elution (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

26 of 26

  • The authors state this as an assumption.

    Recovery of radioactivity corresponded to recovery of apoE mass.

    “Assuming that recovery of radioactivity corresponded to the recovery of apoE mass, the specific activities could be estimated with 7,500 cpm/ng.”

  • The paper relies on this without support.

    The proposed receptor-binding domain of apoE includes residue 146.

    “at amino acid position 146 in the proposed receptor-binding domain of apoE.”

  • The authors state this as an assumption.

    Heparin can serve as a model for negatively charged cell surface proteoglycans.

    “heparin was used as a model for negatively charged cell surface proteoglycans.”

  • The paper relies on this without support.

    Heparin binding is a valid model for apoE binding to cell surface proteoglycans.

    “we analyzed the binding of apoE-3, apoE-2(Arg '58-Cys), and apoE-1 (Lys 46--Glu) to heparin as a model for cell surface proteoglycans.”
4 of 4

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?

  • The K146E mutation impairs both LDLR and HSPG binding.

    “we exploited the K146E mutation, which impairs both LDLR and HSPG binding36.”

    From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [36]

    The Results report impaired LDL-receptor binding and show that K146E binding to heparin fell to 10% of normal. Heparin was used as a model for cell-surface proteoglycans; the Discussion proposes impaired binding to HSPG but does not report a direct HSPG-binding test. The claim states that proposed impairment as an established finding. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Lipid-bound apoE3[K146E] has less than 10% binding capacity to the LDL receptor and HSPG compared with apoE3.

    “Lipid-bound apoE3[K146E] had less than 10% binding capacity to the LDL receptor and HSPG compared with apoE3 [34], [35], [36].”

    From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [35]

    The Results (Fibroblast binding; page not supplied) report 7.7±0.8% LDL-receptor binding for apoE-1 (Lys146→Glu) relative to apoE-3. The Results (Heparin binding; page not supplied) report 10% binding to heparin-Sepharose, used as a model for cell-surface proteoglycans. Thus, the source supports less than 10% for LDL-receptor binding, but reports 10%, not less than 10%, for the proteoglycan model and does not report a direct HSPG-binding measurement. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Heterozygosity for apoE3[K146E] with the apoE3 allele results in dominant expression of type III HLP.

    “Finally, heterozygosity for the apoE variant apoE3[K146E] with the apoE3 allele resulted in a dominant expression of type III HLP [33], [34], [35].”

    From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [35]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Subject 1 apoE-3 distribution exceeds 100%

    Minor

    The five reported lipoprotein percentages for subject 1's apoE-3 sum to 101.9%, not 100%.

    Reported 100 · recomputed 101.9

  • ApoE-1 binding-activity uncertainty differs between text and table

    Minor

    The Results text gives the apoE-1 relative binding activity as 7.7±0.8%, whereas Table IV gives 7.7±0.7%.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Mahley, R. W., and S. C. Rall, Jr. 1989. Type m hyperlipoproteinemia (dysbetalipoproteinemia): the role of apolipoprotein E in normal and abnormal lipoprotein metabolism. In The Metabolic Basis of Inherited Disease, 6th ed. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, editors. McGraw-Hill, New York. 1195-1213.
  2. Gregg, R. E., D. Wilson, E. Rubalcaba, R. Ronan, and H. B. Brewer, Jr. 1983. Immunoquantitation of apolipoprotein E. In Proceedings of the Workshop on Apolipoprotein Quantification. K. Lippel, editor. National Institutes of Health Publication 83-1266, Bethesda, MD. 383-401.

Cited by

Sorted by citations

Related

Authors
Mann, W. A., Lohse, P., Gregg, R. E., Ronan, R., Hoeg, J. M., Zech, L. A., & Brewer, H. B.
Affiliations
National Institutes of Health (US)
ORCID
Gregg, R E
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1995-08-01
Volume
96
Issue
2
Pages
1100-1107
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci118096
PMC
PMC185299
OpenAlex
W2132023886
Cited by
28
References
58
Citations by year
2025: 2 · 2024: 1 · 2022: 3 · 2021: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 1
FWCI
1.53
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • NIH Clinical Center
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
type III hyperlipoproteinemia, apolipoprotein E, dominant inheritance, LDL receptor binding, plasma residence time, heparin binding, APOE isoforms
MeSH terms
Adult, Alleles, Apolipoproteins E, Cells, Cultured, DNA Mutational Analysis, Female, Fibroblasts, Genes, Dominant, Heparin, Humans, Hyperlipoproteinemia Type III, Kinetics, Male, Protein Binding, Receptors, LDL, Structure-Activity Relationship, Point Mutation

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.

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