Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127
Open accessAbstract
Apolipoprotein (apo) E3-Leiden is a variant of apoE that is associated with dominant expression of type III hyperlipoproteinemia and that is defective in binding to the low density lipoprotein receptor. Therefore, the structure of apoE3-Leiden was investigated. Upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis apoE3-Leiden and its 22-kDa amino-terminal thrombolytic fragment migrated with a higher than normal apparent molecular weight. The structural abnormality of apoE3-Leiden was determined by sequencing its CNBr-, tryptic-, and Staphylococcus aureus V8 protease-generated peptides. In contrast to normal apoE3, which has a cysteine at residue 112, apoE3-Leiden does not contain any cysteine and has an arginine at position 112 (as does apoE4, which also completely lacks cysteine). The basis for the molecular weight difference was determined to be a seven-amino acid insertion that is a tandem repeat of residues 121-127 of normal apoE3, i.e. Glu-Val-Gln-Ala-Met-Leu-Gly, resulting in apoE3-Leiden having 306 amino acids rather than 299. The negatively charged glutamyl residues within the insertion compensates for the arginine substitution at residue 112; thus apoE3-Leiden focuses in the E3 position. The low density lipoprotein receptor binding activities of both intact apoE3-Leiden and its 22-kDa thrombolytic fragment were determined in an in vitro assay. Although apoE3-Leiden had only about 25% of normal binding activity, its 22-kDa thrombolytic fragment had nearly normal binding, suggesting that the carboxyl-terminal domain of apoE3-Leiden modulates the receptor binding function of its amino-terminal domain.
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Written from the paper’s full text.
TL;DR
Apolipoprotein E3-Leiden differs from normal apoE3 by an arginine-for-cysteine substitution at residue 112 and a seven-amino acid insertion that is a tandem repeat of residues 121–127. Intact apoE3-Leiden has about 25% of normal LDL receptor binding activity, whereas its 22-kDa thrombolytic fragment binds nearly normally, suggesting the carboxyl-terminal domain modulates amino-terminal receptor binding.
Key findings
- ApoE3-Leiden contains no cysteine and has arginine at position 112, as in apoE4; it focuses in the E3 position because the negatively charged glutamyl residue in the insertion compensates for the arginine substitution.
- The variant has a seven-amino acid insertion, Glu-Val-Gln-Ala-Met-Leu-Gly, which is a tandem repeat of residues 121–127 of normal apoE3, giving apoE3-Leiden 306 amino acids rather than 299; the added mass is calculated as 729 Da.
- Intact apoE3-Leiden·DMPC complexes had about 25% of normal apoE3 receptor binding activity, calculated from the 50% competition point, while the 22-kDa thrombolytic fragment of apoE3-Leiden had nearly normal binding.
- In the V. kindred, six of eight family members examined were heterozygous for apoE3-Leiden and expressed type III hyperlipoproteinemia; the two unaffected family members were homozygous for normal apoE3.
Methods
- ApoE3-Leiden was isolated from d < 1.02 g/ml lipoproteins from the propositus (subject II-6 in the V. kindred) and characterized by SDS-polyacrylamide gel electrophoresis, analytical isoelectric focusing, and preparative Immobiline isoelectric focusing.
- Structural analysis used CNBr digestion, thrombin digestion, tryptic digestion, and Staphylococcus aureus V8 protease digestion, followed by Sephadex G-50 chromatography, two-dimensional paper peptide mapping, reverse-phase HPLC, amino acid analysis, and automated peptide sequencing.
- Receptor binding assays used cultured human fibroblasts with 125I-labeled LDL as competitor; apoE·DMPC complexes were tested, and each point represents the average of two independent experiments.
Limitations
- The paper states that the mechanism accounting for the seven-residue repeated sequence is not known; it discusses recombination and replication slippage as possibilities and notes that DNA sequence analysis confirmed a 21-base pair duplication corresponding to amino acids 121–127 or 120–126, cited as a manuscript in preparation.
- The paper does not include a dedicated limitations section. Evident from the text: receptor binding data are from an in vitro fibroblast competition assay with each point representing the average of two independent experiments, and the total isolated apoE used for binding consisted of at least 90% variant apoE3-Leiden and was used directly without further purification.
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6 of 66 cited sources checked · 6 supported · 0 flagged
- Premisecitation§ DISCUSSION · p. 5
The mutations of apoE3(112 Cys→Arg, 142 Arg→Cys) and apoE1-Harrisburg(146 Lys→Glu) occur within a putative α-helix (residues 131-150).
“In contrast, the mutations of both apoE3(112 Cys→Arg, 142 Arg→Cys) (10) and apoE1-Harrisburg(146 Lys→Glu) (11) occur within a putative α-helix (residues 131-150) (25), which is rich in basic amino acids that are thought to provide direct ionic interaction with the acidic residues within the ligand binding domain of the LDL receptor (31).”
Quote in the paperNot a substantial claim1 of 3 sources checked - Findingown data§ MATERIALS AND METHODS · p. 2
The amino acid compositions of the 22-kDa thrombolytic fragments of apoE3-Leiden and normal apoE3 showed no readily apparent differences.
“This was also the case when the amino acid compositions of the respective 22kDa thrombolytic fragments were compared (data not shown).”
Quote in the paperNot a substantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
The apoE3-Leiden T15* peptide contains the normal T15 sequence with the 7-residue sequence Glu-Val-Gln-Ala-Met-Leu-Gly inserted after Gly-127.
“Inspection of this sequence also indicated that this peptide contains the normal T15 sequence, with the 7-residue sequence Glu-Val-Gln-AlaMet-Leu-Gly inserted after Gly-127.”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
Two new peptides were found on the apoE3-Leiden V8 map compared with the normal apoE3 map.
“Two new peptides were found on the apoE3-Leiden map compared with the normal apoE3 map (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
A variety of other thrombolytic, CNBr, tryptic, and V8 peptides encompassing almost the entire apoE sequence showed no other differences from normal apoE.
“A variety of other thrombolytic, CNBr, tryptic, and V8 peptides encompassing almost the entire apoE sequence showed no other differences from normal apoE (data not shown).”
Quote in the paperSubstantial claim
- Findingown data§ MATERIALS AND METHODS · p. 3
The expected normal V8 peptide encompassing residues 122-132 was also found on the apoE3-Leiden map.
“The expected normal peptide encompassing residues 122-132 was also found on the apoE3-Leiden map (V8 17, Table I).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 4
The 7-residue sequence Glu-Val-Gln-Ala-Met-Leu-Gly encompassing residues 121-127 in normal apoE3 is directly repeated in apoE3-Leiden.
“Second, the 7-residue sequence Glu-Val-Gln-Ala-Met-Leu-Gly encompassing residues 121-127 in normal apoE3 is directly repeated in apoE3Leiden, resulting in a variant protein that is seven amino acids longer than normal (306 versus 299).”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
A new basic V8 peptide encompassed residues 110-121 and resulted from the substitution of arginine for cysteine at position 112 in apoE3-Leiden.
“A new basic peptide was found that encompassed residues 110-121 and resulted from the substitution of arginine-for-cysteine at position 112 in apoE3-Leiden (V8 16, Table I).”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
ApoE3-Leiden·DMPC complexes were defective in binding to LDL receptors on human fibroblasts.
“As shown in Fig. 6, the apoE3-Leiden·dimyristoylphosphatidylcholine (DMPC) complexes were defective in binding to the LDL receptors on human fibroblasts, in agreement with the findings of Havekes and co-workers (1, 2), who used apoE3-Leiden·egg phosphatidylcholine complexes.”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingcitation§ DISCUSSION · p. 5
DNA sequence analysis has confirmed the presence of a 21-base pair duplication that corresponds to amino acids 121-127 (or 120-126).
“DNA sequence analysis has confirmed the presence of a 21-base pair duplication that corresponds to amino acids 121-127 (or 120-126).2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
- Findingcitation§ MATERIALS AND METHODS · p. 2
After cysteine residues were modified with cysteamine, only a small portion of apoE3-Leiden shifted to the E4 position.
“After cysteine residues were modified with cysteamine (7), only a small portion shifted to the E4 position (Fig. 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Weisgraber, 1982, J. Biol. Chem. source
- Findingcitation§ MATERIALS AND METHODS · p. 2
The gel filtration separation profile of the CNBr peptides of apoE3-Leiden is similar to that for normal apoE3 except for the presence of a new peak (CBX) eluting at the column volume.
“This profile is similar to that for normal apoE3 (17, 23) except for the presence of a new peak (CBX) eluting at the column volume.”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data§ MATERIALS AND METHODS · p. 3
The tryptic map of apoE3-Leiden has three new peptides compared with the tryptic map of normal apoE3.
“There were three new peptides present on the apoE3-Leiden map (Fig. 4) as compared with the tryptic map of normal apoE3.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 4
In apoE3-Leiden, arginine replaces cysteine at residue 112.
“First, as is the case in apoE4, arginine replaces cysteine at residue 112, making it likely that apoE3- Leiden is derived from the €4 allele.”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
The sequence of the second new acidic peptide, T15*, identified the position of the 7-residue CBX sequence in apoE3-Leiden.
“The sequence of the second new acidic peptide, labeled T15* (Fig. 4), identified the position of the 7-residue CBX sequence in apoE3Leiden.”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION · p. 4
ApoE3-Leiden is seven amino acids longer than normal apoE3 (306 versus 299 residues).
“Second, the 7-residue sequence Glu-Val-Gln-Ala-Met-Leu-Gly encompassing residues 121-127 in normal apoE3 is directly repeated in apoE3Leiden, resulting in a variant protein that is seven amino acids longer than normal (306 versus 299).”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION · p. 5
Removal of the carboxyl-terminal domain in apoE3-Leiden increases the receptor binding activity from 25% of normal to nearly normal.
“Removal of the carboxylterminal domain in this variant increases the receptor binding activity from 25% of normal to nearly normal.”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
A new acidic V8 peptide with the sequence Val-Gln-Ala-Met-Leu-Gly-Glu resulted from the introduction of a new glutamyl cleavage site within the insertion.
“A new acidic peptide with the sequence Val-Gln-Ala-Met-Leu-Gly-Glu resulted from the introduction of a new glutamyl cleavage site within the insertion (V8 17*, Table I).”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 2
Upon SDS-polyacrylamide gel electrophoresis, apoE3-Leiden migrated as a single band with an apparent molecular mass approximately 1-2 kDa greater than normal apoE3.
“When apoE3-Leiden, isolated from the d < 1.02 g/ml lipoproteins of the propositus of the V. kindred, was subjected to SDS-polyacrylamide gel electrophoresis, a single band with an apparent molecular mass approximately 1-2 kDa greater than normal apoE3 was seen (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 2
The new CNBr fragment CBX has the sequence LeuGly-Glu-Val-Gln-Ala-Met.
“The composition of the new CNBr fragment, CBX, is given in Table I, and its sequence was LeuGly-Glu-Val-Gln-Ala-Met.”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 2
The apoE3-Leiden peptide corresponding to CB5 (residues 126-218 in normal apoE) was sequenced for 61 cycles and was identical to that of normal apoE3.
“The peptide corresponding to CB5 (residues 126-218 in normal apoE) was sequenced for 61 cycles and was found to be identical to that of normal apoE3 (data not shown).”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION · p. 4
The primary structure of apoE3-Leiden differs from normal apoE3 in two respects.
“The primary structure of apoE3-Leiden differs from normal apoE3 in two respects.”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
The 7-residue insertion in apoE3-Leiden is a direct repeat of the preceding 7 residues, which are residues 121-127 in normal apoE.
“This 7-residue insertion is a direct repeat of the preceding 7 residues, which are residues121-127 in normal apoE.”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION · p. 4
The additional mass that the repeated segment adds to apoE3-Leiden is calculated to be 729 Da.
“The additional mass that this repeated segment adds to the variant is calculated to be 729 Da, and both apoE3-Leiden and its 22-kDa thrombolytic fragment display increased apparent molecular masses on SDS-polyacrylamide gels (Fig. 1).”
Quote in the paperNot a substantial claim - Findingown data§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
The molecular weight difference of apoE3-Leiden is due to a seven-amino acid insertion that is a tandem repeat of residues 121-127 of normal apoE3, i.e. Glu-Val-Gln-Ala-Met-Leu-Gly.
“The basis for the molecular weight difference was determined to be a seven-amino acid insertion that is a tandem repeat of residues 121127 of normal apoE3, i.e. Glu-Val-Gln-Ala-Met-LeuGly, resulting in apoE3-Leiden having 306 amino acids rather than 299.”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 2
In the gel system described, apoE3-Leiden is the only apoE variant to have a different electrophoretic mobility.
“In the gel system described under”
Quote in the paperNot a substantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
ApoE3-Leiden possesses about 25% of normal apoE3 receptor binding activity, calculated from the 50% competition point.
“A logitlog plot of the binding data in Fig. 6 indicated that apoE3Leiden possesses about 25% of normal apoE3 receptor binding activity (calculated from the 50% competition point).”
Quote in the paperSubstantial claim - Findingown data§ MATERIALS AND METHODS · p. 3
Two-dimensional paper mapping of S. aureus V8 proteolytic peptides confirmed the results.
“Two-dimensional paper mapping of the S. aureus V8 proteolytic peptides confirmed these results.”
Quote in the paperSubstantial claim - Findingown data§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
ApoE3-Leiden has 306 amino acids rather than 299.
“The basis for the molecular weight difference was determined to be a seven-amino acid insertion that is a tandem repeat of residues 121127 of normal apoE3, i.e. Glu-Val-Gln-Ala-Met-LeuGly, resulting in apoE3-Leiden having 306 amino acids rather than 299.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION · p. 4
The CNBr peptide CB5 was sequenced for 61 cycles and was found to be identical to that of normal apoE3.
“Likewise, the CNBr peptide CB5 was sequenced for 61 cycles and was found to be identical to that of normal apoE3.”
Quote in the paperNot a substantial claim - Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
Type III hyperlipoproteinemia is associated with genetic mutants of apoE that bind defectively to lipoprotein receptors.
“Type III hyperlipoproteinemia is associated with genetic mutants of apoE that bind defectively to lipoprotein receptors (3, 4).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Mahley, 1984, Adv. Intern. Med.
Not checked in the free run.
- cites [4] Mahley, 1989
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ DISCUSSION · p. 5
In the absence of the carboxyl-terminal domain, the amino-terminal domain of apoE3-Leiden can assume a conformation that allows nearly normal binding to occur.
“However, in the absence of the carboxyl-terminal domain, the amino-terminal domain of apoE3-Leiden can assume a conformation that allows nearly normal binding to occur.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION · p. 4
Because the positively charged arginine at residue 112 is compensated for by the negatively charged glutamic acid residue contained within the insertion, apoE3-Leiden focuses in the apoE3 position.
“Because the positively charged arginine at residue 112 is compensated for by the negatively charged glutamic acid residue contained within the insertion, this variant focuses in the apoE3 position.”
Quote in the paperSubstantial claim - Premisecitation§ MATERIALS AND METHODS · p. 3
The total isolated apoE consisted of at least 90% of the variant apoE3-Leiden isoform.
“Because the total isolated apoE consisted of at least 90% of the variant apoE3Leiden isoform (2), it was used directly, without further purification, for receptor binding analysis in an in vitro assay (21).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ DISCUSSION · p. 5
Residues 121-127 in apoE3 constitute nearly two full turns of a predicted α-helix.
“Residues 121– 127 in apoE3 constitute nearly two full turns of a predicted α-helix (12).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Wetterau, 1988, J. Biol. Chem. source
- Premisecitation§ MATERIALS AND METHODS · p. 1
Apolipoprotein E3-Leiden, after being purified and recombined with egg phosphatidylcholine, was defective in binding to LDL receptors on both cultured human fibroblasts and HeLa cells.
“Apolipoprotein E3-Leiden, after being purified and recombined with egg phosphatidylcholine, also was defective in binding to LDL receptors on both cultured human fibroblasts and HeLa cells (1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ MATERIALS AND METHODS · p. 3
One new acidic peptide and the new basic peptide, labeled T13* and T13**, respectively, arose as a result of the arginine-for-cysteine substitution at position 112, yielding a new tryptic cleavage site in apoE3-Leiden.
“One of the new acidic peptides and the new basic peptide, labeled T13* and T13**, respectively (Fig. 4), arose as a result of the arginine-for-cysteine substitution at position 112, yielding a new tryptic cleavage site in apoE3-Leiden.”
Quote in the paperNot a substantial claim - Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
The apoE3-Leiden mutant constituted the vast majority of the total apoE in affected subjects.
“In addition, the apoE3-Leiden mutant constituted the vast majority of the total apoE in affected subjects (2), indicating that it is either produced at a greater rate than the normal isoform or is catabolized at a much slower rate.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
- Premisecitation§ DISCUSSION · p. 5
The carboxyl-terminal domain of apoE can modulate the receptor binding function of the amino-terminal domain.
“Even though the amino- and carboxyl-terminal structural domains of apoE appear to be independently folded (12, 29), evidence suggests that the carboxyl-terminal domain can modulate the receptor binding function of the amino-terminal domain (25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Innerarity, 1984, J. Biol. Chem. source
- Interpretationown data§ MATERIALS AND METHODS · p. 2
The property responsible for the aberrant electrophoretic mobility of apoE3-Leiden resides within the 22-kDa thrombolytic fragment.
“This indicated that the property responsible for the aberrant electrophoretic mobility of this variant resided within the 22-kDa thrombolytic fragment.”
Quote in the paperSubstantial claim - Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
A third variant, apoE1-Harrisburg(146 Lys→Glu), results in dominant expression of type III hyperlipoproteinemia in five family members from three generations when heterozygous.
“A third such variant is apoE1-Harrisburg(146 Lys→Glu); heterozygosity for this variant results in dominant expression of type III hyperlipoproteinemia in five family members from three generations (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Mann, 1989, Clin. Res.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
The carboxyl-terminal domain of apoE3-Leiden modulates the receptor binding function of its amino-terminal domain.
“suggesting that the carboxyl-terminal domain of apoE3-Leiden modulates the receptor binding function of its aminoterminal domain.”
Quote in the paperSubstantial claim- Rests on an assumption: The 22-kDa thrombolytic fragment of apoE corresponds to the amino-terminal domain, and the 12-kDa fragment corresponds to the carboxyl-terminal domain.
- Interpretationreasoning§ DISCUSSION · p. 4
ApoE3-Leiden is likely derived from the ε4 allele.
“First, as is the case in apoE4, arginine replaces cysteine at residue 112, making it likely that apoE3- Leiden is derived from the €4 allele.”
Quote in the paperNot a substantial claim - Interpretationown data§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
The seven-amino acid insertion appears to be responsible for an unusual characteristic of apoE3-Leiden receptor binding.
“In this report we describe a new type of apoE mutation, in which an insertion of seven amino acids appears to be responsible for an unusual characteristic of apoE3-Leiden receptor binding.”
Quote in the paperSubstantial claim - Interpretationcitation§ DISCUSSION · p. 5
Removal of the carboxyl-terminal one-third of the molecule releases some constraint on the receptor binding function of the amino-terminal domain.
“This indicates that removal of the carboxyl-terminal one-third of the molecule releases some constraint on the receptor binding function of the amino-terminal domain.”
Quote in the paperSubstantial claim - Interpretationcitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1
Other factors, environmental or genetic, are required for expression of type III hyperlipoproteinemia in individuals homozygous for apoE2(158 Arg→Cys).
“Therefore, not only is the mode of inheritance recessive, but other factors, environmental or genetic, are required for expression of type III hyperlipoproteinemia in these individuals (8, 9).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Utermann, 1982, Ric. Clin. Lab. source
- cites [9] Utermann, 1985
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning§ DISCUSSION · p. 5
There are five possible positions where 21 nucleotides could be repeated tandemly to give the new protein sequence.
“The situation is even more complex at the nucleotide level: there are five possible positions where 21 nucleotides could be repeated tandemly to give the new protein sequence.”
Quote in the paperNot a substantial claim - Premisecitation§ DISCUSSION · p. 5
The cysteamine-treated apoE2 22-kDa thrombolytic fragment possesses full receptor binding activity.
“More importantly, the cysteamine-treated apoE2 22-kDa thrombolytic fragment possesses full receptor binding activity (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Innerarity, 1984, J. Biol. Chem. source
- Interpretationreasoning§ DISCUSSION · p. 5
The repetition of residues 121-127 in apoE3-Leiden is predicted to increase the length of this helix by two turns.
“The repetition of these residues in apoE3-Leiden would therefore be predicted to increase the length of this helix by two turns.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION · p. 5
The β-VLDL isolated from this patient after weight loss possessed a 30-fold higher receptor binding activity than the β-VLDL isolated before weight loss.
“The β-VLDL isolated from this patient after weight loss possessed a 30-fold higher receptor binding activity than the β-VLDL isolated before weight loss (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Innerarity, 1986
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation§ DISCUSSION · p. 5
The binding activity of β-VLDL isolated from a single type III hyperlipoproteinemic patient homozygous for apoE2(158 Arg→Cys) before and after dietary intervention has been shown to vary.
“For example, the binding activity of β-VLDL isolated from a single type III hyperlipoproteinemic patient homozygous for apoE2(158 Arg→Cys) before and after dietary intervention has been shown to vary (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Innerarity, 1986
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation§ DISCUSSION · p. 5
Type III hyperlipoproteinemia is transmitted in a dominant fashion in this family.
“Although the affected subjects are heterozygous for apoE3Leiden, they all express type III hyperlipoproteinemia (2), indicating that this lipid disorder is transmitted in a dominant fashion in this family.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
- Interpretationreasoning§ DISCUSSION · p. 5
One factor that may influence dominant versus recessive expression of type III hyperlipoproteinemia is the location of the mutation in the apoE polypeptide chain.
“One factor that may influence dominant versus recessive expression of type III hyperlipoproteinemia is the location of the mutation in the apoE polypeptide chain.”
Quote in the paperSubstantial claim
- May combine two claims. 30
- Classified as probably not a substantial claim. 13
- The quote only partly states this claim. 1
May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1The apoE3(112 Cys→Arg, 142 Arg→Cys) and apoE1-Harrisburg(146 Lys→Glu) mutants are defective in their interaction with the LDL receptor.
“These latter two mutants are also defective in their interaction with the LDL receptor (10, 11).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [10] Rall, 1989, J. Clin. Invest. source
- cites [11] Mann, 1989, Clin. Res.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1A second variant that results in a dominant mode of expression of type III hyperlipoproteinemia is apoE3(112 Cys→Arg, 142 Arg→Cys); six family members from four generations are heterozygous for this variant and express type III hyperlipoproteinemia, whereas family members lacking this variant do not express the disorder.
“A second variant that results in a dominant mode of expression of type III hyperlipoproteinemia is apoE3(112 Cys→Arg, 142 Arg→Cys) (10). Six family members from four generations are heterozygous for this variant and express type III hyperlipoproteinemia, whereas family members lacking this variant do not express the disorder (10).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [10] Rall, 1989, J. Clin. Invest. source
May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1Three other apoE variants display an absolute correlation between the presence of only one allele for the variant and the occurrence of type III hyperlipoproteinemia, indicating that these mutants are associated with dominant, rather than recessive, expression of this disorder.
“In contrast to apoE2(158 Arg→Cys), three other apoE variants display an absolute correlation between the presence of only one allele for the variant and the occurrence of type III hyperlipoproteinemia, indicating that these mutants are associated with dominant, rather than recessive, expression of this disorder (2, 10, 11).”
Quote in the paperNot a substantial claim1 of 3 sources checkedMay combine two claims.
Premisecitation§ DISCUSSION · p. 5There are two other apoE mutants for which dominant expression of type III hyperlipoproteinemia also appears to be the case: apoE3(112 Cys→Arg, 142 Arg→Cys) and apoE1-Harrisburg(146 Lys→Glu).
“There are two other apoE mutants for which this also appears to be the case: apoE3(112 Cys→Arg, 142 Arg→Cys) (10) and apoE1-Harrisburg(146 Lys→Glu) (11).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [10] Rall, 1989, J. Clin. Invest. source
- cites [11] Mann, 1989, Clin. Res.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ DISCUSSION · p. 6Heterozygosity for apoE2(145 Arg→Cys), apoE2(146 Lys→Gln), or apoE2-Christchurch(136 Arg→Ser) is associated with type III hyperlipoproteinemia.
“While heterozygosity for three further mutants (apoE2(145 Arg→Cys) (32, 33), apoE2(146 Lys→Gln) (34), or apoE2-Christchurch(136 Arg→Ser) (18, 33)) is associated with type III hyperlipoproteinemia, there are no family studies to ascertain whether these variants also demonstrate a dominant mode of inheritance.”
Quote in the paperNot a substantial claim1 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ MATERIALS AND METHODS · p. 2Upon isoelectric focusing, apoE3-Leiden focused in the E3 position.
“Upon isoelectric focusing, apoE3-Leiden focused in the E3 position (Fig. 2), in agreement with previous reports (1, 2).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 3The apoE3-Leiden peptide T15* was a 22-residue peptide with the sequence Gly-Glu-Val-Gln-Ala-Met-Leu-Gly-Glu-Val-Gln-Ala-Met-Leu-Gly-Gln-Ser-Thr-Glu-Glu-Leu-Arg, which contained the CBX sequence in its entirety.
“However, the apoE3Leiden peptide T15* was a 22-residue peptide (Table I) with the sequence Gly-Glu-Val-Gln-Ala-Met-Leu-Gly-Glu-ValGln-Ala-Met-Leu-Gly-Gln-Ser-Thr-Glu-Glu-Leu-Arg, which contained the CBX sequence in its entirety.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 3Two of the new tryptic peptides had net negative charge, and one had net positive charge.
“Two of these new peptides had net negative charge, and one had net positive charge (Table I).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 2When apoE3-Leiden was digested with thrombin, its amino-terminal 22-kDa fragment displayed a slower electrophoretic mobility than the normal apoE3 22-kDa fragment, while its carboxyl-terminal 12-kDa fragment migrated identically to the 12-kDa fragment from normal apoE3.
“When apoE3-Leiden was digested with thrombin, the amino-terminal22-kDa fragment also displayed a slower electrophoretic mobility than the normal apoE3 22-kDa fragment, while the carboxyl-terminal 12-kDa fragment of apoE3-Leiden migrated in a position identical to the 12-kDa fragment from normal apoE3 (Fig. 1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSION · p. 4Both apoE3-Leiden and its 22-kDa thrombolytic fragment display increased apparent molecular masses on SDS-polyacrylamide gels.
“The additional mass that this repeated segment adds to the variant is calculated to be 729 Da, and both apoE3-Leiden and its 22-kDa thrombolytic fragment display increased apparent molecular masses on SDS-polyacrylamide gels (Fig. 1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 3When the 22-kDa thrombolytic fragment of apoE3-Leiden was complexed with DMPC, its receptor binding activity was nearly identical to normal apoE3·DMPC and the normal apoE3 22-kDa thrombolytic fragment.
“In contrast, when the 22-kDa thrombolytic fragment of apoE3Leiden was complexed with DMPC, its receptor binding activity was nearly identical to normal apoE3·DMPC (Fig. 6) and the normal apoE3 22-kDa thrombolytic fragment (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Innerarity, 1983, J. Biol. Chem. source
May combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 2Sequencing confirmed that apoE3-Leiden CB4 had arginine at the position corresponding to residue 112, as occurs in apoE4, which also completely lacks cysteine.
“This difference was confirmed by sequencing: apoE3-Leiden CB4 had arginine at the position corresponding to residue 112, just as occurs in apoE4, which also completely lacks cysteine.”
Quote in the paperSubstantial claimMay combine two claims.
Findingcitation§ DISCUSSION · p. 5The affected subjects are heterozygous for apoE3-Leiden and all express type III hyperlipoproteinemia.
“Although the affected subjects are heterozygous for apoE3Leiden, they all express type III hyperlipoproteinemia (2), indicating that this lipid disorder is transmitted in a dominant fashion in this family.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
May combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 2Amino acid analysis of the apoE3-Leiden peptide corresponding to CB4 indicated an absence of cysteine but the presence of an extra arginine.
“Amino acid analysis of the apoE3-Leiden peptide corresponding to CB4 (residues 109-125 in normal apoE) indicated an absence of cysteine but the presence of an extra arginine (Table I).”
Quote in the paperSubstantial claimMay combine two claims.
Findingcitation§ MATERIALS AND METHODS · p. 2The minor band that shifted to the E4 position after cysteamine treatment contained 1.3 mol of cysteine (determined as cysteic acid)/mol of protein, confirming that the second allelic product expressed in the propositus is normal apoE3.
“Amino acid analysis of this material showed that it contained 1.3 mol of cysteine (determined as cysteic acid)/ mol of protein, confirming that the second allelic product expressed in the propositus is normal apoE3 (2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
May combine two claims.
Findingown data§ MATERIALS AND METHODS · p. 2ApoE3-Leiden did not contain cysteine, and no other compositional differences from normal apoE3 were readily apparent.
“It was found that apoE3-Leiden did not contain cysteine, but no other compositional differences were readily apparent (data not shown).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ DISCUSSION · p. 4The tryptic peptide T14 is identical to that of normal apoE3.
“The tryptic peptide T14 is identical to that of normal apoE3 and is not included in Table I but is given here for completeness.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1Although about 1% of the population is homozygous for apoE2(158 Arg→Cys), only a small fraction of these individuals develop hyperlipidemia, even though all possess β-VLDL.
“Furthermore, although ~1% of the population is homozygous for apoE2(158 Arg→Cys), only a small fraction of these individuals develop hyperlipidemia, even though all possess β-VLDL (8, 9).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8] Utermann, 1982, Ric. Clin. Lab. source
- cites [9] Utermann, 1985
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1Defective binding of apoE mutants to lipoprotein receptors causes impaired clearance of chylomicron and very low density lipoprotein remnants (β-VLDL), which accumulate in plasma and cause hypercholesterolemia and hypertriglyceridemia.
“This defective binding causes impaired clearance of chylomicron and very low density lipoprotein remnants (β-VLDL) (5, 6), which accumulate in the plasma and cause both hypercholesterolemia and hypertriglyceridemia.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1Apolipoprotein E3-Leiden is a variant of apoE that is associated with dominant expression of type III hyperlipoproteinemia and is defective in binding to the low density lipoprotein receptor.
“Apolipoprotein (apo) E3-Leiden is a variant of apoE that is associated with dominant expression of type III hyperlipoproteinemia and that is defective in binding to the low density lipoprotein receptor.”
- Also stated in: § Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1 · plain
“Apolipoprotein (apo)¹ E3-Leiden is a rare variant of apoE that is associated with the lipid disorder type III hyperlipoproteinemia and that has an impaired ability to bind to the low density lipoprotein (LDL) receptor on cultured human fibroblasts and HeLa cells (1, 2).”
Quote in the paperSubstantial claim0 of 2 sources checked- Also stated in: § Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1 · plain
May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1apoE2(158 Arg→Cys) is associated with a recessive mode of inheritance of type III hyperlipoproteinemia; the vast majority of type III subjects are homozygous for it, and heterozygotes almost never develop the disorder.
“This variant is associated with a recessive mode of inheritance of type III hyperlipoproteinemia; the vast majority of all type III subjects are homozygous for apoE2(158 Arg→Cys), and heterozygotes almost never develop the disorder (4).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Mahley, 1989
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1The most common apoE variant associated with type III hyperlipoproteinemia is apoE2(158 Arg→Cys), which exhibits only about 1% of the in vitro receptor binding activity of normal apoE3.
“The most common apoE variant associated with this disorder is apoE2(158 Arg→Cys) (4), which exhibits only ~1% of the in vitro receptor binding activity of normal apoE3 (7).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [4] Mahley, 1989
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7] Weisgraber, 1982, J. Biol. Chem. source
May combine two claims.
Premisecitation§ MATERIALS AND METHODS · p. 1All six individuals possessing the mutant apoE3-Leiden isoform had β-VLDL and elevated plasma concentrations of cholesterol, triglycerides, and apoE.
“All six individuals possessing the mutant apoE3-Leiden isoform had β-VLDL and elevated plasma concentrations of cholesterol, triglycerides, and apoE (2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
May combine two claims.
Premisecitation§ MATERIALS AND METHODS · p. 1Four individuals had xanthomas, including palmar xanthomas, which have been described only in type III hyperlipoproteinemia.
“In addition, four individuals had xanthomas, including palmar xanthomas (2), which have been described only in type III hyperlipoproteinemia (4).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
- cites [4] Mahley, 1989
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationreasoning§ DISCUSSION · p. 6In the case of apoE3-Leiden, the nature of the mutation, a 7-amino acid insertion, probably causes a permanent disruption in the receptor binding domain and therefore leads to dominant expression of type III hyperlipoproteinemia.
“In the case of apoE3-Leiden, the nature of the mutation, a 7-amino acid insertion, probably causes a permanent disruption in the receptor binding domain and therefore leads to dominant expression of type III hyperlipoproteinemia.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationcitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1The apoE3-Leiden mutant is either produced at a greater rate than the normal isoform or is catabolized at a much slower rate.
“In addition, the apoE3-Leiden mutant constituted the vast majority of the total apoE in affected subjects (2), indicating that it is either produced at a greater rate than the normal isoform or is catabolized at a much slower rate.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
May combine two claims.
Interpretationreasoning§ DISCUSSION · p. 5The carboxyl-terminal domain of apoE3-Leiden appears to modulate the receptor binding function of its amino-terminal domain, although the mechanism is likely different from that for apoE2(158 Arg→Cys).
“Likewise, the carboxyl-terminal domain of apoE3-Leiden also appears to modulate the receptor binding function of its amino-terminal domain, although the mechanism is likely to be different than that for apoE2(158 Arg→Cys).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5The amino- and carboxyl-terminal structural domains of apoE appear to be independently folded.
“Even though the amino- and carboxyl-terminal structural domains of apoE appear to be independently folded (12, 29), evidence suggests that the carboxyl-terminal domain can modulate the receptor binding function of the amino-terminal domain (25).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ MATERIALS AND METHODS · p. 2Havekes et al. reported that apoE3-Leiden has a retarded mobility, migrating between normal apoE3 and apoE2(158 Arg→Cys), in another gel system in which apoE2(158 Arg→Cys) has a retarded mobility.
“In another gel system in which apoE2(158 Arg→Cys) has a retarded mobility (22), Havekes et al. (2) have reported that apoE3-Leiden also has a retarded mobility, migrating between normal apoE3 and apoE2(158 Arg→Cys).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5The apoE2 22-kDa amino-terminal thrombolytic fragment displays a 12-fold increase in binding to the LDL receptor.
“However, the apoE2 22-kDa amino-terminal thrombolytic fragment displays a 12-fold increase in binding to the LDL receptor (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Innerarity, 1984, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5When the cysteine at position 158 of apoE2 is converted to a positively charged lysine analogue by reaction with cysteamine, this apoE2 possesses ~13% of the receptor binding activity of normal apoE3.
“Similarly, when the cysteine at position 158 of apoE2 is converted to a positively charged lysine analogue by reaction with cysteamine, this apoE2 possesses ~13% of the receptor binding activity of normal apoE3 (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Innerarity, 1984, J. Biol. Chem. source
May combine two claims.
Interpretationreasoning§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1The negatively charged glutamyl residue within the insertion compensates for the arginine substitution at residue 112; thus apoE3-Leiden focuses in the E3 position.
“The negatively charged glutamyl residue within the insertion compensates for the arginine substitution at residue 112; thus apoE3-Leiden focuses in the E3 position.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Mark R. Wardell‡, Karl H. Weisgraber, Louis M. Havekes§, and Stanley C. Rall, Jr. · p. 1The first example of dominant expression was established in two generations of the apoE3-Leiden (V.) kindred; six of eight family members examined are heterozygous for this variant and express type III disease, and the two unaffected family members are homozygous for normal apoE3.
“The first example was established in two generations of the apoE3-Leiden (V.) kindred (2). Six of eight family members examined are heterozygous for this variant and express type III disease (2). The two unaffected family members are homozygous for normal apoE3.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Havekes, 1986, Hum. Genet. source
May combine two claims. The quote only partly states this claim.
Interpretationreasoning§ MATERIALS AND METHODS · p. 3Although apoE3-Leiden has arginine at position 112, making it E4-like, it focuses in the same position as normal apoE3 because of the presence of the negatively charged glutamic acid residue in the 7-residue insertion.
“Although apoE3-Leiden has arginine at position 112, making it”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5The receptor binding activity of apoE2(158 Arg→Cys)·DMPC is only 1% of normal apoE3·DMPC.
“The receptor binding activity of apoE2(158 Arg→Cys)·DMPC is only 1% of normal apoE3.DMPC (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Weisgraber, 1982, J. Biol. Chem. source
Classified as probably not a substantial claim.
Premisecitation§ MATERIALS AND METHODS · p. 3In normal apoE3, peptide T15 is a 15-residue peptide encompassing residues 120-134.
“In normal apoE3, peptide T15 is a 15-residue peptide encompassing residues 120-134 (23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Rall, 1982, J. Biol. Chem. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSION · p. 5The putative α-helix (residues 131-150) is rich in basic amino acids that are thought to provide direct ionic interaction with the acidic residues within the ligand binding domain of the LDL receptor.
“In contrast, the mutations of both apoE3(112 Cys→Arg, 142 Arg→Cys) (10) and apoE1-Harrisburg(146 Lys→Glu) (11) occur within a putative α-helix (residues 131-150) (25), which is rich in basic amino acids that are thought to provide direct ionic interaction with the acidic residues within the ligand binding domain of the LDL receptor (31).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationreasoning§ DISCUSSION · p. 5The susceptibility of apoE2(158 Arg→Cys) to environmental influences on its receptor binding activity may be the explanation for its association with a recessive mode of inheritance of type III hyperlipoproteinemia.
“The susceptibility of this apoE variant to environmental influences on its receptor binding activity may be the explanation for its association with a recessive mode of inheritance of type III hyperlipoproteinemia.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationcitation§ DISCUSSION · p. 5Different lipid environments within lipoprotein particles could alter the conformation of the receptor binding domain of apoE2(158 Arg→Cys) and affect its binding activity.
“This result suggests that different lipid environments within lipoprotein particles could alter the conformation of the receptor binding domain of apoE2(158 Arg→Cys) and affect its binding activity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ DISCUSSION · p. 5The site of the mutation may determine whether the receptor binding activity can be modulated by other factors.
“The site of the mutation may determine whether the receptor binding activity can be modulated by other factors.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ DISCUSSION · p. 5As a result of the diet, the subject's plasma cholesterol concentration decreased drastically (from 725 to 92 mg/dl) and the ratio of cholesterol to triglyceride in his VLDL (d < 1.006 g/ml) decreased 3-fold.
“As a result of the diet, the subject's plasma cholesterol concentration decreased drastically (from 725 to 92 mg/dl) and the ratio of cholesterol to triglyceride in his VLDL (d < 1.006 g/ ml) decreased 3-fold (30).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Innerarity, 1986
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
The 22-kDa thrombolytic fragment of apoE corresponds to the amino-terminal domain, and the 12-kDa fragment corresponds to the carboxyl-terminal domain.
“When apoE3-Leiden was digested with thrombin, the amino-terminal22-kDa fragment also displayed a slower electrophoretic mobility than the normal apoE3 22-kDa fragment, while the carboxyl-terminal 12-kDa fragment of apoE3-Leiden migrated in a position identical to the 12-kDa fragment from normal apoE3 (Fig. 1).”
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 Leiden is characterized by defective receptor binding.
“In in vitro assays, apoE Leiden is defective in its affinity for the low density lipoprotein (LDL) receptor (6, 11, 14)”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [14]
In in vitro assays, apoE Leiden is defective in its affinity for the LDL receptor, having about 25% of normal apoE3 binding affinity.
“In in vitro assays, apoE Leiden is defective in its affinity for the low density lipoprotein (LDL) receptor (6, 11, 14), having about 25% of normal apoE3 binding affinity.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [14]
ApoE Leiden is characterized by a tandem repetition of amino acids 121-127 and has arginines at both polymorphic sites 112 and 158.
“ApoE Leiden, one of the most thoroughly studied of the rare apoE variants (6, 11, 12), is characterized by the presence of a tandem repetition of amino acids 121-127 and has arginines at both polymorphic sites 112 and 158 (13, 14).”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [14]
ApoE Leiden is considerably more active in receptor binding than apoE2, which exhibits less than 2% of normal apoE3 binding.
“ApoE Leiden is considerably more active in receptor binding than apoE2 (6, 14), which exhibits less than 2% of normal apoE3 binding.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [14]
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- Authors
- Wardell, M. R., Weisgraber, K. H., Havekes, L. M., & Rall, S. C.
- Affiliations
- University of California, San Francisco (US)
- Netherlands Organisation for Applied Scientific Research (NL)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1989-12
- Volume
- 264
- Issue
- 35
- Pages
- 21205-21210
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1537162160
- Semantic Scholar
- 081df5a1cdca911f10e52c042fdd76428ca19c9d
- Cited by
- 80
- References
- 29
- Citations by year
- 2026: 1 · 2024: 1 · 2021: 1 · 2018: 1 · 2016: 3 · 2015: 1 · 2013: 1 · 2012: 1
- FWCI
- 8.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- TNO Repository (submittedVersion)
- Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- National Heart, Lung, and Blood Institute (HL-41633)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, type III hyperlipoproteinemia, amino acid insertion, tandem repeats, cysteine substitution, protein structure, C-terminal domain, N-terminal domain, molecular weight
- MeSH terms
- Amino Acid Sequence, Apolipoproteins E, Chromatography, Gel, Cyanogen Bromide, DNA Transposable Elements, Electrophoresis, Polyacrylamide Gel, Humans, Isoelectric Focusing, Molecular Sequence Data, Molecular Weight, Peptide Fragments, Peptide Mapping, Repetitive Sequences, Nucleic Acid, Thrombin, Genetic Variation, Apolipoprotein E3
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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.
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