Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia.
Open accessAbstract
The primary structure of apolipoprotein E (apo E) was investigated in seven type III hyperlipoproteinemic patients with the apo E-2/2 phenotype. Six of the patients had identical two-dimensional tryptic peptide maps. These differed from the normal apo E3 map by the altered mobility of a single peptide. Amino acid analysis and sequencing showed that apo E2 in these patients had a substitution of 158 Arg----Cys. The presence of this mutation in six of the seven type III patients confirms that this is the most common form of apo E2. The seventh type III patient had a unique map with a new peptide resulting from a substitution of 136 Arg----Ser. He was heterozygous for this and for the more common apo E2 (158 Arg----Cys) variant. His very low-density lipoprotein contained approximately five times more apo E2 (136 Arg----Ser) than apo E2 (158 Arg----Cys), as determined by cysteamine treatment and peptide mapping. This new apo E2 mutant thus appears to contribute significantly to the patient's hyperlipidemia.
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Claims the paper makes
4 of 45 cited sources checked · 4 supported · 0 flagged
- Premisecitation
The heparin-binding and receptor-binding domains coincide.
“This is significant because the heparin-binding and receptor-binding domains coincide (59).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [59] 59. Weisgraber, K. H., S. C. Rall, Jr., R. W. Mahley, R. W. Milne, Y. L. Marcell, and J. T. Sparrow. 1986. Human apolipoprotein E: de- termination of the heparin binding sites of apolipoprotein E3. J. Biol. Chem. 261:2068-2076. source
- Findingown data
Quantitative amino acid analysis of the daughter's T17Ch and T17 peptides gave a ratio of 1.5 to 1.
“When quantitative amino acid analysis was performed on her two peptides, T17Ch and T17, the ratio was found to be 1.5:1.”
Quote in the paperSubstantial claim - Findingown data
The seventh type III patient had a unique peptide map with a new peptide caused by an arginine-to-serine substitution at position 136.
“The seventh type III patient had a unique map with a new peptide resulting from a substitution of 136 Arg --Ser.”
Quote in the paperSubstantial claim - Findingown data
The seventh type III patient was heterozygous for the 158 Arg->Cys mutation and for a new variant, apo E2 (136 Arg->Ser).
“The seventh type III patient was heterozygous for this and for a new variant, apo E2 (136 Arg --Ser).”
Quote in the paperSubstantial claim - Findingown data
The ratio of peptide T17Ch to T17 was 4.8 to 1.
“The ratio of T17Ch to T17 was 4.8:1”
Quote in the paperSubstantial claim
- Findingown data
In those six patients, apo E2 had an arginine-to-cysteine substitution at position 158.
“Amino acid analysis and sequencing showed that apo E2 in these patients had a substitution of 158 Arg --Cys.”
- Also stated in: § Results · boosted
“confirming the substitution as 158 Arg --Cys.”
Quote in the paperSubstantial claim - Also stated in: § Results · boosted
- Findingown data
The seventh patient's VLDL contained about five times more apo E2(136 Arg->Ser) than apo E2(158 Arg->Cys), as measured by cysteamine treatment and peptide mapping.
“His very low-density lipoprotein contained approximately five times more apo E2 (136 Arg -Ser) than apo E2 (158 Arg --Cys), as determined by cysteamine treatment and peptide mapping.”
Quote in the paperSubstantial claim - Findingown data
The initial amino acid sequence of peptide T17 was Leu-Ala.
“The expected initial sequence of Leu-Ala was confirmed for T 17”
Quote in the paperNot a substantial claim - Findingown data
The initial amino acid sequence of peptide T17Ch was Val-Ser-Leu.
“that of TI 7Ch was Val-Ser-Leu”
Quote in the paperSubstantial claim - Findingown data
Tryptic peptide T17Ch from the proband contained two extra amino acids, valine and serine.
“that T17Ch contained two additional amino acids, valine and serine.”
Quote in the paperSubstantial claim - Findingown data
All seven type III patients had the apo E-2/2 phenotype by analytical isoelectric focusing.
“All seven type III patients were shown to have the apo E- 2/2 phenotype by analytical isoelectric focusing.”
Quote in the paperSubstantial claim - Findingown data
The ratio of peptide T22 to CM-T22* was 4.9 to 1.
“and the ratio of T22 to CM-T22* was 4.9: 1.”
Quote in the paperSubstantial claim - Findingown data
The peptide maps of those six patients differed from the normal apo E3 map because one peptide had altered mobility.
“These differed from the normal apo E3 map by the altered mobility of a single peptide.”
Quote in the paperSubstantial claim - Findingown data
In six unrelated patients with type III hyperlipoproteinemia and the apo E-2/2 phenotype, their apo E2 was identical to the most common postulated apo E2 variant.
“In each of six unrelated patients with type III hyperlipoproteinemia and the apo E-2/2 phenotype, we showed that their apo E2 was identical to that which has been postulated as the most common apo E2 variant (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] 24. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apoli- poprotein E2. Evidence for modulation of the binding site conformation. J.Biol. Chem. 259:7261-7267. source
- Findingown data
In this study, six of the seven type III patients were homozygous for apo E2(158 Arg->Cys).
“In this investigation, six ofseven type III patients were found to be homozygous for apo E2 (158 Arg -o Cys), confirming this as the most common apo E2 isoform.”
- Also stated in: § Results · boosted
“The complete absence of the normal T22 peptide indicated that these six individuals were in fact homozygous for apo E2 (158 Arg --Cys).”
Quote in the paperSubstantial claim - Also stated in: § Results · boosted
- Findingown data
With cysteamine, the apo E isoform pattern from six of the seven type III patients migrated two charge units more cathodally, indicating two cysteine residues.
“With cysteamine, the apo E isoform pattern from six ofthe seven type III patients migrated two charge units more cathodally, indicating the presence oftwo cysteine residues”
Quote in the paperSubstantial claim - Findingown data
The complete absence of the normal T22 peptide indicated that the six individuals were homozygous for apo E2(158 Arg->Cys).
“The complete absence of the normal T22 peptide indicated that these six individuals were in fact homozygous for apo E2 (158 Arg --Cys).”
Quote in the paperSubstantial claim - Findingown data
In six of the seven patients with type III hyperlipoproteinemia and the apo E-2/2 phenotype, the two-dimensional tryptic peptide maps were identical.
“Six of the patients had identical two-di- mensional tryptic peptide maps.”
Quote in the paperSubstantial claim - Findingown data
The daughter of the seventh patient, who had the apo E-3/2 phenotype, also carried the new protein.
“His daughter, who had the apo E-3/2 phenotype, also possessed the new protein.”
Quote in the paperNot a substantial claim - Findingown data
Amino acid analysis of T22 and CM-T22* indicated that they were identical except that CM-T22* contained an additional carboxymethyl cysteine.
“Amino acid analysis of T22 and CM-T22* (Table III) in- dicated that they were identical, except that CM-T22* contained an additional residue ofcarboxymethyl cysteine.”
Quote in the paperSubstantial claim - Findingown data
The seventh patient was heterozygous for the new apo E2(136 Arg->Ser) and the more common apo E2(158 Arg->Cys) variant.
“He was heterozygous for this and for the more common apo E2 (158 Arg --Cys) variant.”
Quote in the paperSubstantial claim - Findingown data
Preliminary experiments in the authors' laboratory showed that apo E2 (158 Arg->Cys) and apo E2 (136 Arg->Ser) have the same heparin affinity when chromatographed on heparin sepharose under denaturing conditions.
“Preliminary experiments in our laboratory have shown that apo E2 (158 Arg -* Cys) and apo E2 (136 Arg --Ser) have the same heparin affinity when chromatographed on heparin seph- arose under denaturing conditions.”
Quote in the paperNot a substantial claim - Findingcitation
J.W.T.'s mean conversion time of VLDL to LDL was 32.7 h, markedly longer than the mean of 27.4±3.02 h for other homozygous apo E-2/2 type III patients.
“Similarly, his mean conversion time of VLDL to LDL (32.7 h) was markedly longer than the mean for other homozygous apo E-2/2 type III patients of 27.4±3.02h (25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] 25. Janus, E. D., S. Grant, L. Sinclair, and R. Wootton. 1986. Apo- lipoprotein B metabolism in type III hyperlipoproteinaemia and in hy- pocholesterolaemic E2/2 subjects. In Proceedings of the Seventh Inter- national Symposium on Atherosclerosis. N. H. Fidge and P. J. Nestel, editors. Elsevier Science Publishers, Amsterdam. 317-320.
Not checked in the free run.
- Findingown data
J.W.T.'s plasma lipoprotein electrophoresis showed a broad beta band characteristic of type III hyperlipoproteinemia.
“J.W.T., showing the broad-,8 band characteristic of type HI hyperlipoproteinemia (arrow).”
Quote in the paperSubstantial claim - Findingcitation
J.W.T. had a markedly reduced VLDL fractional catabolic rate of 0.045 h-1, compared with other type III patients with the apo E-2/2 phenotype whose mean was 0.078±0.018 h-1.
“The lipoprotein turnover studies showed J.W.T. had a markedly reduced VLDL fractional cat- abolic rate (0.045 h-'), compared with other type HI patients with the apo E-2/2 phenotype (mean = 0.078±0.018h-') (25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] 25. Janus, E. D., S. Grant, L. Sinclair, and R. Wootton. 1986. Apo- lipoprotein B metabolism in type III hyperlipoproteinaemia and in hy- pocholesterolaemic E2/2 subjects. In Proceedings of the Seventh Inter- national Symposium on Atherosclerosis. N. H. Fidge and P. J. Nestel, editors. Elsevier Science Publishers, Amsterdam. 317-320.
Not checked in the free run.
- Findingown data
In J.W.T.'s daughter, who has the apo E-3/2 phenotype, apo E2 (136 Arg->Ser) represented 60% of the apo E circulating in her VLDL.
“In the daughter of J.W.T., who has the apo E-3/2 phenotype, apo E2 (136 Arg --Ser) only represented 60% of the apo E circulating in her VLDL.”
Quote in the paperNot a substantial claim - Interpretationown data
The new apo E2(136 Arg->Ser) mutant appears to contribute substantially to the seventh patient's hyperlipidemia.
“This new apo E2 mutant thus appears to contribute significantly to the patient's hyperlipidemia.”
Quote in the paperSubstantial claim- Rests on an assumption: The relative amount of apo E2(136 Arg->Ser) versus apo E2(158 Arg->Cys) in VLDL reflects the mutant's contribution to the patient's hyperlipidemia.
- Interpretationown data
A cysteine-for-arginine substitution at position 158 is the most common mutation producing the apo E2 isoprotein.
“We thus confirm that a substitution of cysteine for arginine at position 158 is the most common mutation giving rise to the apo E2 isoprotein.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] 24. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apoli- poprotein E2. Evidence for modulation of the binding site conformation. J.Biol. Chem. 259:7261-7267. source
- Interpretationreasoning
Peptide T17 is the only possible source of the new basic peptide T17Ch.
“This leaves T 17 as the only possible source of the new peptide.”
Quote in the paperSubstantial claim- Rests on an assumption: There are only two histidine-containing peptides in apo E, T17 and T39.
- Interpretationreasoning
The loss of positive charge from peptide T39 could only produce a new acidic peptide, not a basic one.
“The loss of positive charge from peptide T39 could only produce a new acidic peptide, and not a basic one.”
Quote in the paperSubstantial claim - Interpretationreasoning
The aberrant peptide T17Ch can result only from mutation of arginine 136 to a neutral residue.
“Considering its electrophoretic mobility (+0.65) and its specific staining characteristics, the aberrant peptide (T17Ch) can result only from the mutation of arginine 136 to a neutral residue.”
Quote in the paperSubstantial claim- Rests on an assumption: There are only two histidine-containing peptides in apo E, T17 and T39.
- Premisenone given
Type III hyperlipoproteinemia is associated with the apo E2 variant.
“Type III is associated with a variant form of apo E, apo E2.”
Quote in the paperSubstantial claim - Interpretationown data
The eldest daughter inherited the apo E2 (136 Arg->Ser) mutant from her father, as shown by the presence of peptide T17Ch.
“The eldest daughter was found to have inherited the apo E2 (136 Arg -* Ser) mutant from her father, as evidenced by the presence of peptide T17Ch.”
Quote in the paperSubstantial claim - Interpretationown data
The Val-Ser-Leu sequence of T17Ch indicates a mutation of arginine 136 to serine.
“indicating a mutation of 136 Arg -> Ser.”
Quote in the paperSubstantial claim - Premisecitation
The receptor-binding domain of apo E lies between residues 140 and 150.
“The determination of receptor-binding affinity of known variants (6,13,14,(19)(20)(21), and the blocking ofreceptor binding by monoclonal antibodies to apo E (22) have established that its receptor-binding domain lies between residues 140 and 150.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites (6,13,14,(19)(20)(21)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [22] 22. Weisgraber, K. H., T. L. Innerarity, K. J. Harder, R. W. Mahley, R. W. Milne, Y. L. Marcel, and J. T. Sparrow. 1983. The receptor- binding domain of human apolipoprotein E. Monoclonal antibody in- hibition of binding. J. Biol. Chem. 258:12348-12354. source
- Interpretationown data
The finding of the 158 Arg-to-Cys mutation in six of the seven type III patients confirms that this is the most common form of apo E2.
“The presence of this mu- tation in six of the seven type III patients confirms that this is the most common form of apo E2.”
Quote in the paperSubstantial claim - Interpretationreasoning
The 136 Arg->Ser substitution can arise from a point mutation of CGC to AGC in the apo E3 gene.
“This substitution can arise from a point mutation of CGC --AGC occurring in the apo E3 gene.”
Quote in the paperNot a substantial claim - Interpretationreasoning
A third histidine would not result in the apo E-2/2 phenotype observed in J.W.T.
“This latter possi- bility can be excluded, because the presence of a third histidine, with its positive charge, would not result in the expression of the apo E-2/2 phenotype observed in J.W.T.”
Quote in the paperSubstantial claim - Interpretationown data
The apo E2 (136 Arg->Ser) variant contributes significantly to the hyperlipidemia in J.W.T.
“Whatever the basis for the relative increase in apo E2 (136 Arg -8 Ser), it is clear that this variant contributes significantly to the hyperlipidemia in J.W.T.”
Quote in the paperSubstantial claim - Premisecitation
A genetically engineered site-directed mutant of 136 Arg->Ser showed only 41% of normal apo E3 receptor binding to apo B,E (LDL) receptors on cultured human fibroblasts.
“However, a genetically engineered site-directed mutant of 136 Arg -* Ser showed only 41% of normal apo E3 receptor binding to apo B,E (LDL) re- ceptors on cultured human fibroblasts (58).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [58] 58. Lalazar, A., K. H. Weisgraber, T. Vogel, H. Giladi, T. L. Inner- arity, R. Otter, M. Zeevi, A. Lezanon, J. K. Boyles, D. Kanner, Z. Yavin, B. Amit, M. Gorecki, and R. W. Mahley. 1987. Analysis of structure- function relationships of human apolipoprotein E via site-directed mu- tagenesis. Fed. Proc. In press.
Not checked in the free run.
- Interpretationreasoning
The preponderance of apo E2 (136 Arg->Ser) is most likely due to a perturbation of protein structure rather than altered gene expression.
“The preponderance of apo E2 (136 Arg -.Ser) is most likely due to a perturbation of protein structure rather than altered gene expression.”
Quote in the paperSubstantial claim - Interpretationreasoning
Increased expression of the apo E2-Christchurch gene as an explanation for its preponderance is improbable.
“church gene cannot be discounted as an explanation, it is im- probable.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Replacing arginine 136 with serine would not be expected to affect the internal stability of the helix.
“Although the replacement of arginine 136 by serine would not be expected to affect the internal stability of the helix”
Quote in the paperSubstantial claim - Interpretationreasoning
Loss of a putative ionic bond involving arginine 136 could be expected to alter the alignment of the helix.
“the loss ofa putative ionic bond involving this arginine could be expected to result in altered alignment of the helix.”
Quote in the paperSubstantial claim
- May combine two claims. 29
- Classified as probably not a substantial claim. 12
May combine two claims.
PremisecitationThe most common apo E2 has a 158 Arg-to-Cys mutation, while 145 Arg-to-Cys and 146 Lys-to-Gln mutations have also been reported in type III hyperlipoproteinemia.
“The most common has a mutation of 158 Arg --Cys (13), but mutations of 145 Arg -* Cys (14) and 146 Lys --Gln (6) have also been reported in individuals with type III hyperlipoproteinemia.”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [13] 13. Rall, S. C., Jr., K. H. Weisgraber, and R. W. Mahley. 1982. Human apolipoprotein E. The complete amino acid sequence. J. Biol. Chem. 257:4171-4178. source
- cites [14] 14. Rall, S. C., Jr., K. H. Weisgraber, T. L. Innerarity, and R. W. Mahley. 1982. Structural basis for receptor binding heterogeneity ofapo- lipoprotein E from type III hyperlipoproteinemic subjects. Proc. Natl. Acad. Sci. USA. 79:4696-4700. source
- cites [6] 6. Rall, S. C., Jr., K. H. Weisgraber, T. L. Innerarity, T. P. Bersot, R. W. Mahley, and C. B. Blum. 1983. Identification of a new structural variant of human apolipoprotein E, E2(Lys 146 -* Gln), in a type III hyperlipoproteinaemic subject with the E-3/2 phenotype. J. Clin. Invest. 72:1288-1297. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThree apo E2 variants have been described, each differing from apo E3 by a single amino acid substitution.
“Three variants ofapo E2 have been described.Each ofthese differs from apo E3 by a single amino acid substitution (6, 12- 14).”
Quote in the paperNot a substantial claim1 of 4 sources checked- cites [6] 6. Rall, S. C., Jr., K. H. Weisgraber, T. L. Innerarity, T. P. Bersot, R. W. Mahley, and C. B. Blum. 1983. Identification of a new structural variant of human apolipoprotein E, E2(Lys 146 -* Gln), in a type III hyperlipoproteinaemic subject with the E-3/2 phenotype. J. Clin. Invest. 72:1288-1297. source
- cites [12] 12. Weisgraber, K. H., S. C. Rall, Jr., and R. W. Mahley. 1981. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J. Biol. Chem. 256: 9077-9083. source
- cites [13] 13. Rall, S. C., Jr., K. H. Weisgraber, and R. W. Mahley. 1982. Human apolipoprotein E. The complete amino acid sequence. J. Biol. Chem. 257:4171-4178. source
- cites [14] 14. Rall, S. C., Jr., K. H. Weisgraber, T. L. Innerarity, and R. W. Mahley. 1982. Structural basis for receptor binding heterogeneity ofapo- lipoprotein E from type III hyperlipoproteinemic subjects. Proc. Natl. Acad. Sci. USA. 79:4696-4700. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIndividual cases of type III have been observed with the apo E-3/3 phenotype and with apo E deficiency.
“Individual cases of type III have also been observed in association with the apo E-3/3 phenotype (9) and in an individual with a deficiency of apo E (10).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [9] 9. Havel, R. J., L. Kotite, J. P. Kane, P. Tun, and T. Bersot. 1983. Atypical familial dysbetalipoproteinemia associated with apolipoprotein phenotype E3/3. J. Clin. Invest. 72:379-387. source
- cites [10] 10. Ghiselli, G., E. J. Schaefer, P. Gascon, and H. B. Brewer, Jr. 1981. Type III hyperlipoproteinemia associated with apolipoprotein E deficiency. Science (Wash. DC). 214:1239-1241. source
May combine two claims.
Findingown dataPeptide T22 was absent in six of the seven homozygous apo E2 type III patients and was replaced by a new tyrosine- and sulfur-containing peptide.
“Peptide T22 was missing in six of the seven homozygous apo E2 type III patients and was replaced by a new peptide containing tyrosine and sulphur.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCysteamine treatment shifted the apo E-3/3 isoform pattern of control subject F.J.T. toward the cathode so that it resembled apo E-4/4, indicating one cysteine residue.
“As expected, cyste- amine treatment caused the apo E-3/3 isoform pattern ofF.J.T. to shift toward the cathode, and thus to resemble the apo E-4/ 4 phenotype.This indicated the presence ofone cysteine residue (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataA considerable excess of apo E2 (136 Arg->Ser) over the usual apo E2 gene product was indicated by cysteamine treatment and peptide mapping and confirmed by quantitative elution and amino acid analysis.
“Both cysteamine treatment and peptide mapping indicated a considerable excess of apo E2 (136 Arg -* Ser) over the usual apo E2 gene product.”
- Also stated in: § Results · plain
“This was confirmed by quantitative elution and amino acid analysis of the appropriate peptides.”
Quote in the paperSubstantial claim- Also stated in: § Results · plain
May combine two claims.
Findingown dataK.T. does not yet show symptoms of type III hyperlipoproteinemia, although her plasma triglyceride increased from 1.4 to 3.8 mmol/liter.
“As yet she does not exhibit any symptoms of type III hyperlipoproteinemia, although her plasma triglyceride has increased from 1.4 to 3.8 mmol/liter.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAmino acid, N-terminal, and sequence analysis confirmed the new cysteine in CM-T22* and established the sequence CM-Cys-Leu-Ala, Val, Tyr, Gln, Ala, Gly, Ala, Arg.
“The im- plied new cysteine in CM-T22* was confirmed by amino acid, N-terminal, and sequence analysis.A sequence/composition of CM-Cys-Leu-Ala, Val, Tyr, Gln, Ala, Gly, Ala, Arg was estab- lished for this aberrant peptide.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataInitial sequences Leu-Ala-Val and CM-Cys-Leu-Ala were obtained for T22 and CM-T22*, confirming the 158 Arg-to-Cys substitution.
“Initial sequences of Leu-Ala-Val and CM-Cys-Leu-Ala respectively were ob- tained for these peptides, confirming the substitution as 158 Arg --Cys.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn J.W.T., cysteamine modification changed a major apo E isoprotein by only one charge toward the cathode, while a minor band focused two charge units more cathodally, indicating two apo E2 proteins: one with two cysteines and one with a single cysteine.
“After cys- teamine modification, a major apo E isoprotein changed its mi- gration by only one charge towards the cathode, whereas a minor band focused two charge units more cathodally (Fig. 1 B).This indicated the presence of two apo E2 proteins: one”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataK.T. had an elevated cholesterol level at age ten, but five years later her cholesterol was normal at 4.4 mmol/liter.
“At the age of ten, K.T. had an elevated cholesterol level, but now, five years later, her cholesterol is normal (4.4 mmol/liter).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataJ.W.T. had a unique peptide map that differed from the other type III maps in two ways: T22 was present in addition to CM-T22*, with T22 in substantially higher yield, and a new basic peptide T17Ch was observed with mobility +0.65 relative to aspartic acid.
“J.W.T. had a unique peptide map that differed from the other type III maps in two respects.First, T22 was present in addition to CM-T22*, the former being present in substantially higher yield.Second, a completely new basic peptide (T17Ch) was observed with a mobility of +0.65 relative to aspartic acid (Fig. 2 C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe seventh patient was heterozygous for apo E2(158 Arg->Cys) and a new apo E2(136 Arg->Ser), and the new variant was the predominant VLDL isoform in him.
“The seventh was hetero- zygous for this and for a new apo E2, apo E2 (136 Arg Ser), which was the predominant VLDL isoform in this subject.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataJ.W.T. was heterozygous for the 158 Arg-to-Cys mutation and for a mutation involving peptide T17.
“J.W.T. was heterozygous for this mutation and for one in- volving peptide T1 7.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe new peptide T17Ch stained slowly with cadmium-ninhydrin, suggesting a valine N-terminal, and stained positively for histidine and arginine.
“This new peptide stained slowly with cadmium-ninhydrin suggesting a valine N-terminal (36) and it also stained positively for histidine and arginine.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn carboxymethylated apo E2 (158 Arg Cys), peptide T22 is missing and is replaced by a new neutral peptide, CM-T22*.
“Peptide T22 is missing and replaced by a new neu- tral peptide, CM-T22*.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe apo E2-Christchurch gene product makes up 80% of the apo E in J.W.T.'s VLDL, with the remaining 20% being apo E2 (158 Arg->Cys).
“A fascinating feature of this case is that the product of the apo E2-Christchurch gene comprises 80% of the apo E in J.W.T.'s VLDL, the remaining 20% being apo E2 (158 Arg Cys).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premiseown dataThe primary structures of nine apo E isoproteins have now been determined.
“The primary structures of nine apo E isoproteins have now been determined (Table IV).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table IV
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationCysteamine adds a positive charge to cysteine residues, and the modified apo E has an altered isoelectric focusing pattern.
“This reagent adds a positive charge to cysteine residues and the resultant modified apo E has an altered pattern on isoelectric focusing (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] 12. Weisgraber, K. H., S. C. Rall, Jr., and R. W. Mahley. 1981. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J. Biol. Chem. 256: 9077-9083. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationApo E3 is the most common form in the population and is regarded as the parent or normal isoform.
“As apo E3 is the most common form in the population (28, 45, 47), it is regarded as the parent (24) or normal isoform (48).”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [28] 28. Wardell, M. R., P. A. Suckling, and E. D. Janus. 1982. Genetic variation in human apolipoprotein E. J. Lipid Res. 23:1174-1182. source
- cites [45] 45. Zannis, V. I., and J. L. Breslow. 1981. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 20: 1033-1041. source
- cites [47] 47. Utermann, G., M. Hees, and A. Steinmetz. 1977. Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature (Lond.). 269:604-607. source
- cites [24] 24. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apoli- poprotein E2. Evidence for modulation of the binding site conformation. J.Biol. Chem. 259:7261-7267. source
- cites [48] 48. Gregg, R. E., L. A. Zech, E. J. Schaefer, and H. B. Brewer, Jr. 1984. Apolipoprotein E metabolism in normalipoproteinaemic human subjects. J. Lipid Res. 25:1167-1176. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe complex isoelectric focusing pattern of apo E results from posttranslational desialylation superimposed on genetic polymorphism.
“The complex isoelectric focusing pattern exhibited by apo E results from posttranslational desialylation superimposed on genetic polymorphism (45,46).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] 45. Zannis, V. I., and J. L. Breslow. 1981. Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 20: 1033-1041. source
- cites [46] 46. Zannis, V. I., P. W. Just, and J. L. Breslow. 1981. Human apo- lipoprotein E isoprotein subclasses are genetically determined. Am. J. Hum. Genet. 33:11-24.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe positively charged arginyl residue at position 158 is thought to maintain the correct conformation of the receptor-binding domain.
“The positively charged arginyl residue at position 158 is thought to maintain the correct conformation of the receptor-binding domain (24).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] 24. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apoli- poprotein E2. Evidence for modulation of the binding site conformation. J.Biol. Chem. 259:7261-7267. source
May combine two claims.
InterpretationreasoningThe absence of peptide T16 (Val-Arg) on peptide mapping is explained by heterozygosity and by the recurrence of the Arg-Val-Arg sequence elsewhere in the molecule.
“The resultant loss of peptide T16 (Val-Arg) was not noted on peptide mapping because ofthe heterozygosity and because the sequence Arg-Val-Arg recurs further along the molecule.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe new 136 Arg->Ser substitution is consistent with the apo E-2/2 phenotype, with cysteamine modification experiments, and with peptide mobility changes on mapping.
“The new 136 Arg Ser substitution is consistent with the apo E-2/2 phenotype, with the cysteamine modification experiments and alterations in peptide mobility observed on mapping.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAffected subjects are often homozygous for apo E2, but heterozygosity for this variant has also been reported in association with the disease.
“Affected subjects are often homozygous for apo E2, but hetero- zygosity for this variant has also been reported in association with this disease (4)(5)(6)(7)(8).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] 4. Breslow, J. L., V. I. Zannis, T. R. SanGiacomo, J. L. Third, T. Tracy, and C. J. Glueck. 1982. Studies offamilial type III hyperlipopro- teinaemia using as a genetic marker the apoE phenotype E2/2. J. Lipid Res. 23:1224-1235. source
- cites [5] 5. Zannis, V. I., and J. L. Breslow. 1985. Genetic mutations affecting human lipoprotein metabolism. Adv. Hum. Genet. 14:125-215 and 383- 386. source
- cites [6] 6. Rall, S. C., Jr., K. H. Weisgraber, T. L. Innerarity, T. P. Bersot, R. W. Mahley, and C. B. Blum. 1983. Identification of a new structural variant of human apolipoprotein E, E2(Lys 146 -* Gln), in a type III hyperlipoproteinaemic subject with the E-3/2 phenotype. J. Clin. Invest. 72:1288-1297. source
Queued — the background check reaches it, usually within a day.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe apo B,E or LDL receptor is present in most tissues, and apo E has much higher affinity than apo B for it because apo E-containing particles can form multiple interactions with several sites on the receptor.
“The first of these, apo B,E or low-density lipoprotein (LDL) receptor, is present in most tissues.Apo E has a much higher affinity than apolipoprotein B for this receptor because of the potential of apo E-containing particles to form multiple interactions with several sites on the receptor (15)(16)(17).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15] 15. Pitas, R. E., T. L. Innerarity, K. S. Arnold, and R. W. Mahley. 1979. Rate and equilibrium constants for binding of apo-E HDLc (a cholesterol-induced lipoprotein) and low density lipoproteins to human fibroblasts: evidence for multiple receptor binding of apo-E HDLc. Proc. Natl. Acad. Sci. USA. 76:2311-2315. source
Checked before — its earlier verdict is held back until a new check runs.
- cites [16] 16. Innerarity, T. L., and R. W. Mahley. 1978. Enhanced binding by cultured human fibroblasts of apo-E-containing lipoproteins as com- pared with low density lipoproteins. Biochemistry. 17:1440-1447. source
- cites [17] 17. Innerarity, T. L., E. S. Kempner, D. Y. Hui, and R. W. Mahley. 1981. Functional unit ofthe low density lipoprotein receptor offibroblasts: a 100,000-dalton structure with multiple binding sites. Proc. Natl. Acad. Sci. USA. 78:4378-4382. source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenApo E binds to two distinct high-affinity receptors that mediate internalization and catabolism of lipoprotein particles.
“Apo E binds to two distinct high-affinity receptors mediating internalization and catabolism oflipoprotein particles.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationPositively charged amino acids in the receptor-binding region form ionic bonds with negatively charged residues in a consensus sequence repeated seven times in the ligand-binding region of the apo B,E (LDL) receptor.
“The positively charged amino acids in this region form ionic bonds with negatively charged residues in the consensus se- quence, which is repeated seven times in the ligand-binding region ofthe apo B,E (LDL) receptor (23).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] 23. Yamamoto, T., C. G. Davis, M. S. Brown, W. J. Schneider, M. L. Casey, J. L. Goldstein, and D. W. Russell. 1984. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 39:27-38. source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe apo E or remnant receptor is found only in hepatic tissues and recognizes particles containing apo E but not apo B.
“The second is the apo E or remnant receptor, which is found in hepatic tissues only and is able to recognize particles containing apo E but not apo B (18).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] 18. Hui, D. Y., T. L. Innerarity, and R. W. Mahley. 1981. Lipoprotein binding to canine hepatic membranes. Metabolically distinct apo-E and apo-B,E receptors. J. Biol. Chem. 256:5646-5655. source
May combine two claims.
PremisecitationType III is currently thought to arise from two genetic defects: one in the apo E structural gene and another that causes hyperlipidemia, likely familial combined hyperlipidemia.
“Type III is currently believed to result from two gene defects, one in the apo E structural gene and the other in a gene causing hyperlipidemia, probably familial combined hyperlipidemia (2, 11).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] 2. Utermann, G., N. Pruin, and A. Steinmetz. 1979. Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man. Clin. Genet. 15:63-72.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11] 11. Hazzard, W. R., G. R. Warnick, G. Utermann, and J. J. Albers. 1981. Genetic transmission of isoapolipoprotein E phenotypes in a large kindred: relationship to dyslipoproteinaemia and hyperlipidaemia. Me- tabolism. 30:79-88. source
May combine two claims.
PremisecitationSecondary structure predictions suggest that position 136 lies in an alpha-helix from residues 130 to 150, which includes the receptor-binding domain from 140 to 150.
“Secondary structure predictions (54,55) suggest that position 136 is part of an a-helix that extends between residues 130 and 150 (13,24), encompassing the receptor-binding domain from 140 to 150 (22).”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [54] 54. Chou, P. Y., and G. D. Fasman. 1974. Conformational parameters for amino acids in helical, 3-sheet, and random coil regions calculated from proteins. Biochemistry. 13:211-222. source
- cites [55] 55. Chou, P. Y., and G. D. Fasman. 1974. Prediction of protein conformation. Biochemistry. 13:222-245. source
- cites [13] 13. Rall, S. C., Jr., K. H. Weisgraber, and R. W. Mahley. 1982. Human apolipoprotein E. The complete amino acid sequence. J. Biol. Chem. 257:4171-4178. source
- cites [24] 24. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apoli- poprotein E2. Evidence for modulation of the binding site conformation. J.Biol. Chem. 259:7261-7267. source
- cites [22] 22. Weisgraber, K. H., T. L. Innerarity, K. J. Harder, R. W. Mahley, R. W. Milne, Y. L. Marcel, and J. T. Sparrow. 1983. The receptor- binding domain of human apolipoprotein E. Monoclonal antibody in- hibition of binding. J. Biol. Chem. 258:12348-12354. source
May combine two claims.
InterpretationreasoningA possible explanation for the different apo E2 isoform ratios in father and daughter is that one normal allele provides enough functional apo E to clear particles, while when both alleles are abnormal a slower removal mechanism allows remnant build-up.
“A possible explanation for the different apo E2 isoform ratios found in the father and daughter is that one normal allele gives enough functional apo E to clear particles, whereas when both alleles are abnormal, another slower mechanism exists for the removal ofthese particles, thus allowing for the build-up oftheir remnants.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThe longer circulatory time of remnants may involve different exchange rates of the two apo E2 isoforms with other lipoprotein classes, or apo E2 (136 Arg->Ser) may have a slower catabolic rate than apo E2 (158 Arg->Cys).
“The longer circulatory time of the remnants may be associated with different exchange rates of the two apo E2 iso- forms with other lipoprotein classes, or apo E2 (136 Arg --Ser) may have a slower catabolic rate than apo E2 (158 Arg -.Cys).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAmong about 300 characterized point mutations in hemoglobin, none increase expression, although missplicing of a pseudo-intron in hemoglobin E decreases expression.
“Of some 300 characterized point mutations in hemoglobin (56), none result in increased expression, though missplicing of a pseudo-intron in hemoglobin E ((#26 Glu -.Lys) results in decreased expression (57).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [56] 56. International Hemoglobin Information Center Variant List. 1985. Hemoglobin. 9:229-298.
Not checked in the free run.
- cites [57] 57. Orkin, S. H., H. H. Kazazian, Jr., S. E. Antonarakis, H. Ostrer, S. C. Goff, and J. P. Sexton. 1982. Abnormal RNA processing due to the exon mutation of (#E-globin gene. Nature (Lond.). 300:768-769. source
May combine two claims.
InterpretationreasoningA substitution at position 136 could alter receptor binding, as occurs with apo E2 (158 Arg->Cys), which also lies outside the recognized receptor-binding domain.
“In this way, a substitution at position 136 could alter receptor binding, as happens in the case of apo E2 (158 Arg -* Cys) (24), which also lies outside the recognized receptor-binding domain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] 24. Innerarity, T. L., K. H. Weisgraber, K. S. Arnold, S. C. Rall, Jr., and R. W. Mahley. 1984. Normalization of receptor binding of apoli- poprotein E2. Evidence for modulation of the binding site conformation. J.Biol. Chem. 259:7261-7267. source
The paper relies on this without support.
The apo E2 variant by itself is not sufficient to cause type III hyperlipoproteinemia; only about 2% of apo E2 homozygotes have the disease.
“The variant apo E2 alone is not sufficient to cause type III, however, as only -2% of all apo E2 homozygotes have this disease.”
The paper relies on this without support.
There are only two histidine-containing peptides in apo E, T17 and T39.
“As there are only two histidine-containing peptides in apo E (T17 and T39), one of these peptides must be implicated, or the mutation has introduced a new histidine.”
The paper relies on this without support.
The relative amount of apo E2(136 Arg->Ser) versus apo E2(158 Arg->Cys) in VLDL reflects the mutant's contribution to the patient's hyperlipidemia.
“His very low-density lipoprotein contained approximately five times more apo E2 (136 Arg -Ser) than apo E2 (158 Arg --Cys), as determined by cysteamine treatment and peptide mapping.This new apo E2 mutant thus appears to contribute significantly to the patient's hyperlipidemia.”
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 subject carried two copies of the APOE3 Christchurch (R136S) mutation.
“She had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid, and limited tau/tangle and neurodegenerative measurements.”
From Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report (2019) · cites this paper as [7]
The Discussion (page not supplied) says the patient was heterozygous for apo E2-Christchurch (R136S) and apo E2 (R158C), not that the patient carried two copies of the Christchurch variant. The Results also identify the patient as J.W.T. and describe him as heterozygous; this paper does not describe the woman in the citing sentence. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAPOE-R136S has severely reduced binding affinity to heparin.
“Notably, the APOE-R136S has severely reduced binding affinity to heparin, as the mutation occurs within the receptor-binding region of APOE36,45,58.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [45]
The Discussion (page unavailable) places residue 136 outside the recognized receptor-binding domain, contrary to the citing sentence’s explanation. It reports that APOE-R136S had the same heparin affinity as another APOE2 variant under denaturing conditions; it does not report severely reduced heparin affinity relative to normal APOE. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredA major functional effect of the R136S mutation is disruption of APOE binding to anionic HSPGs on the cell surface.
“A major functional effect of the R136S mutation is disruption of its binding to anionic HSPGs on cell surface36,45.”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [45]
The Results identify the Arg136→Ser substitution, and the Discussion says it could alter receptor binding. But the Discussion does not establish disrupted binding to cell-surface HSPGs; its preliminary heparin-affinity comparison was with another APOE2 variant under denaturing conditions. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBy substituting a positively charged arginine residue for the uncharged serine, the affinity of the receptor-binding domain of APOE-R136S for negatively charged HSPGs is greatly diminished.
“by substituting a positively charged arginine residue for the uncharged serine, the affinity of the receptor-binding domain of APOE-R136S for negatively charged HSPGs is greatly diminished36,45,58”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [45]
The Results identify the Arg136→Ser substitution, and the Discussion says it could alter receptor binding. But the paper does not show that APOE-R136S has greatly diminished affinity for HSPGs. Its preliminary heparin experiment compares the variant with another APOE2 variant, not with unmutated APOE, and finds equal affinity under denaturing conditions (Discussion; page unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredHeterozygosity for apoE3[R136S] with the apoE2 allele results in type III HLP.
“Specifically, heterozygosity for the apoE variant apoE3[R136S] (previously designated apoE2 Christchurch) with the apoE2 allele results in type III HLP [27].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [27]
The Introduction and Discussion report a patient with type III HLP who carried both apoE2 (158 Arg→Cys) and apoE2-Christchurch (136 Arg→Ser), supporting the reported association. But the Introduction says an apoE2 variant alone is not sufficient to cause type III HLP and proposes an additional genetic defect. The source therefore does not establish that this allele combination necessarily results in the disease. (LLM, conf=0.86)
Experimental — accuracy not yet measured
p.Arg154Cys is located in the critical APOE domain and alters the amino acid residue in which another variant, p.Arg154Ser, was found to be likely pathogenic for FD.
“This variant is located in the critical APOE domain [45,46] and alters the amino acid residue, in which another variant, p.Arg154Ser, was found to be likely pathogenic for FD [5,29,47].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [47]
The Results identify an APOE Arg136Ser variant, and the Discussion says it contributes significantly to hyperlipidemia in a patient with familial type III hyperlipoproteinemia. The paper does not use the p.Arg154Ser numbering or establish that it denotes the same residue, so our copy cannot fully verify that specific part of the claim. The critical-domain assertion is attached to other citations in the citing sentence. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCertain other apoE variants are associated with a dominant mode of inheritance, i.e., heterozygosity is sufficient for expression of type III hlp.
“In contrast, certain other apoE variants are associated with a dominant mode of inheritance (5-10), i.e., heterozygosity for these apoE variants is sufficient for the expression of type III hlp.”
From Preferential association of apolipoprotein E Leiden with very low density lipoproteins of human plasma. (1993) · cites this paper as [7]
The Introduction reports that heterozygosity for apoE2 has been observed in people with type III hyperlipoproteinemia, supporting an association. It does not establish that heterozygosity is sufficient or that these variants have a dominant mode of inheritance. The Results describe a daughter who inherited apoE2-Christchurch but had no symptoms of type III hyperlipoproteinemia. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRare APOE variants associated with dominant type III HLPs include APOE2 Heidelberg (Arg136Cys), APOE2 Christchurch (Arg136Ser), APOE2 (Arg142Cys), APOE2 (Arg142Leu), APOE2 (Lys146Gln), and APOE1 Harrisburg (Lys146Glu).
“Rare APOE variants associated with dominant type III HLPs include single-nucleotide substitutions at APOE2 Heidelberg (Arg136Cys)47), APOE2 Christchurch (Arg136Ser)26, 48), APOE2 (Arg142Cys)49, 50), APOE2 (Arg142Leu)51), APOE2 (Lys146Gln)45), and APOE1 Harrisburg (Lys146Glu)52, 53) (Table 2, Fig.5).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [48]
The Abstract and Discussion (page unavailable) identify APOE2-Christchurch as the Arg136Ser variant in a patient with type III hyperlipoproteinemia. The paper does not establish that Christchurch causes dominant type III disease: the patient also carried another APOE2 variant, and the Results report that his daughter inherited Christchurch but had no symptoms of type III hyperlipoproteinemia. This citation is attached to Christchurch, not to the other variants in the list. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe APOE Christchurch variant rs121918393 and the APOE Jacksonville variant rs199768005 are protective against Alzheimer's disease in Caucasians.
“The Christchurch variant rs121918393 (APOEChc: CGC > aGC, p.Arg[R]136Ser[S]) [19–21] and the Jacksonville variant rs199768005 (APOEJax: GTG > GaG, p.Val[V]236Glu[E]) [22, 23] have been identified as protective variants against AD in Caucasians”
From Genetics of Alzheimer’s disease: An East Asian perspective (2023) · cites this paper as [19]
The Discussion identifies APOE2-Christchurch as an Arg136Ser variant arising from a CGC-to-AGC substitution. The cited paper studies type III hyperlipoproteinemia, not protection against Alzheimer’s disease in Caucasians; it also does not give the rs identifier. This citation is attached to the Christchurch variant, not the separately cited Jacksonville variant. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWhole exome sequencing confirmed the subject's PSEN1 E280A mutation and found that she had two copies of the rare APOE3 Christchurch mutation.
“Whole exome sequencing corroborated her PSEN1 E280A mutation and discovered that she had two copies of the rare Christchurch (APOEch)7 mutation (an arginine-to-serine substitution at amino acid 136, corresponding to codon 154) in APOE3.”
From Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report (2019) · cites this paper as [7]
APOE R136S is a very rare mutation (0.0004% allele frequency in the European population) that was originally described in APOEε2 alleles of people with type III hyperlipoproteinaemia, but is much more common in APOEε3 homozygotes than in any other genotype and has also been associated with increased plasma apolipoprotein B levels.
“APOE R136S is a very rare mutation (0.0004% allele frequency in the European population37) that was originally described in APOEε2 alleles of people with type III hyperlipoproteinaemia38,39, but is much more common in APOEε3 homozygotes than in any other genotype and has also been associated with increased plasma apolipoprotein B (APOB) levels37.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [38]
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.
One treated patient's triglycerides conflict with the claim of normal levels
MinorThe paper says treatment brought all seven patients' plasma triglycerides to normal values, but Table I lists J.S.F.'s post-treatment value as 6.6 mmol/liter. Elsewhere, it describes J.W.T.'s similar pretreatment level of 6.7 mmol/liter as high.
“All were undergoing dietary and clofibrate treatment that had successfully lowered their plasma cholesterol and triglyceride levels to normal values (Table I).”
“J.S.F. 30 M 194 84.5 E-2/2 9.5 15.8 6.9 6.6”
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“…allele frequency in the European population 37 ) that was originally described in APOE ε2 alleles of people with type III hyperlipoproteinaemia 38,39 , but is much more common in APOE ε3 homozygotes than in any other genotype and has also been associated with increased plasma apolipoprotein B…”
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“This specific incidence of resilience was attributed to the presence of a homozygous APOE variant known as the Christchurch mutation [23] that confers reductions in low-density lipoprotein receptor and heparin binding [20], implicating these mechanisms as putative drivers of resilience in the face of high amyloid depo…”
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“15 The R136S Christchurch mutation is located in the domain involved in the interaction between ApoE and heparan sulfate proteoglycans (HSPG)andinthebindingtothelow-densitylipoprotein(LDL)andLDL receptor-related protein (LRP) receptors.”
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Self-citationApolipoprotein E Phenotyping: A Word of Caution
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Characterization of a new apolipoprotein E5 variant detected in two French-Canadian subjects
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“The Christchurch mutation results in a Arg136Ser substitution [18].”
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“Mutations in apoE that prevent its binding to the low-density lipoprotein (LDL) receptor and possibly other receptors are associated with type III hyperlipoproteinemia and premature atherosclerosis (6-14).”
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The clinical and laboratory investigation of dysbetalipoproteinemia
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“Using the isoelectric focusing techniques [45] at least four different bands (corresponding to different ApoE2 conformational status) have been identified: E2 (arg158to-cys) [46], E2 (lys146-to-gln) [47], E2 (arg145-to-cys), and E2-Christchurch (arg136-to-ser) [48].”
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Self-citationMolecular Biology of Human Apolipoproteins B and E and Associated Diseases of Lipoprotein Metabolism
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Antigen-specific age-related memory CD8 T cells induce and track Alzheimer’s-like neurodegeneration
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“This protection was evidently afforded by a second germline mutation in the ApoE3 gene that disrupts lipid metabolism (7), highlighting the possibility that the pathogenic effects of A β may be dominantly inhibited by preexisting physiological processes upstream of A β .”
Heidemann, B. E., Koopal, C., Baass, A., Defesche, J. C., Zuurbier, L., Mulder, M. T., Roeters van Lennep, J. E., Riksen, N. P., Boot, C., Marais, A. D., et al. (2022) · Clinical Genetics · doi:10.1111/cge.14185 · Cited by 27 · see citing works
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Civeira, F., Cenarro, A., Ferrando, J., Puzo, J., García-Otín, A. L., Mozas, P., & Pocovı́, M. (1999) · American Heart Journal · doi:10.1016/s0002-8703(99)70262-0 · Cited by 26 · see citing works
Role of Apolipoprotein E in Alzheimer’s Disease
Zannis, V. I., Zanni, E. E., Makrides, S. C., Kardassis, D., & Aleshkov, S. B. (1998) · Springer eBooks · doi:10.1007/978-1-4899-0133-0_13 · Cited by 26 · see citing works
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“Multiple rare APOE coding risk variants have also been identified, including the APOE-e1 Weisgraber allele (Asp127–Cys158) [64], APOE-e1y (Arg112–Cys158) [65], several forms of APOE-e5 (including Lys3 and Arg84–Arg112) [66,67], APOE-e7 (Lys244–Lys245) [68], and the Christchurch mutation (R136S or Ser136) [69], which p…”
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“The R145C variant reduces the positive charge of this domain,(8,21) because it has 40% of the binding affinity of ApoE3 to the LDL receptor.(8,21) This discrepancy in disease manifestation might be explained by considering the role of other ApoE receptors in the clearance of remnant particles from the circulation, inc…”
InfluentialMärz, W., Hoffmann, M. M., Scharnagl, H., Fisher, E., Chen, M., Nauck, M., Feussner, G., & Wieland, H. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33303-4 · Cited by 21 · see citing works
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Identification of apolipoprotein E polymorphism by using synthetic oligonucleotides.
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Yang, Y.-W., Chan, L., & Li, W. (1991) · Journal of Molecular Evolution · doi:10.1007/bf02102649 · Cited by 20 · see citing works
“136, 140, 142, 143, 145, 150, and 158 of the human mature peptide)as crucial residues involved in receptor binding (Wardell et al. 1987; Lalazar et al. 1988).”
BackgroundAtherogenic Lipoproteins Resulting from Genetic Defects of Apolipoproteins B and E
Weisgraber, K. H., Innerarity, T. L., Rall, S. C., & Mahley, R. W. (1990) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1990.tb42274.x · Cited by 20 · see citing works
Hernandez, I., Gelpi, E., Molina‐Porcel, L., Bernal, S., Rodríguez‐Santiago, B., Dols‐Icardo, O., Ruiz, A., Alcolea, D., Boada, M., Lleó, A., et al. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12670 · Cited by 19 · see citing works
de Knijff, P., van den Maagdenberg, A. M. J. M., Boomsma, D. I., Stalenhoef, A. F. H., Smelt, A. H. M., Kastelein, J. J. P., Marais, A. D., Frants, R. R., & Havekes, L. M. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117443 · Cited by 19 · see citing works
Mailly, F., Davignon, J., & Nestruck, A. C. (1990) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)42769-5 · Cited by 19 · see citing works
Current insights into apolipoprotein E and the immune response in Alzheimer's disease
Lin, P. B., & Holtzman, D. M. (2024) · Immunological Reviews · doi:10.1111/imr.13414 · Cited by 19 · see citing works
“88 In the UK biobank study with 455,306 participants, the frequency of APOEch is approximately 0.004%, where the variant is enriched in the APOE3/E3 genotype.”
InfluentialEbert, D. L., Maeda, N., Lowe, S. W., Hasler‐Rapacz, J., Rapacz, J., & Attie, A. (1988) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38429-7 · Cited by 17 · see citing works
“biguously shown to be the domain responsible for apoE binding to the LDL receptor (6-10).”
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Phenotyping of apolipoprotein E by immunoblotting in immobilized pH gradients
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Idenitification and characterization of a new variant of apolipoprotein E (apo E-Kochi).
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Human apolipoprotein E glycosylation and sialylation: from structure to function
Moon, H.-J., Luo, Y., Chugh, D., & Zhao, L. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1399965 · Cited by 18 · see citing works
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Increased serum remnant lipoproteins in patients with apolipoprotein E7 (apo ESuita)
Yanagi, K., Yamashita, S., Hiraoka, H., Ishigami, M., Kihara, S., Hirano, K.-I., Sakai, N., Nozaki, S., Funahashi, T., Kameda-Takemura, K., et al. (1997) · Atherosclerosis · doi:10.1016/s0021-9150(96)06068-6 · Cited by 16 · see citing works
- Authors
- Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R., & Carrell, R. W.
- Affiliations
- Christchurch Hospital (NZ)
- Venue
- Journal of Clinical Investigation
- Published
- 1987-08-01
- Volume
- 80
- Issue
- 2
- Pages
- 483-490
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC442261
- OpenAlex
- W1978899417
- Cited by
- 159
- References
- 61
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 9 · 2023: 6 · 2022: 10 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 1 · 2016: 4 · 2015: 2 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 16.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart Foundation of New Zealand
- 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, apolipoprotein E2, type III hyperlipoproteinemia, apolipoprotein E3, tryptic peptide mapping, VLDL, heterozygous mutation, hyperlipidemia
- MeSH terms
- Adult, Amino Acid Sequence, Apolipoproteins E, Female, Humans, Hyperlipoproteinemia Type III, Male, Middle Aged, Mutation, Pedigree, Peptide Mapping, Receptors, Cell Surface, Low Density Lipoprotein Receptor-Related Protein-1
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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 2026-10-01.
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