The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index; 4 of the 27 sources its claims cite were checked for support.
Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the APOE p.Leu167del Mutation
Open accessAbstract
Apolipoprotein (apo) E mutants are associated with type III hyperlipoproteinemia characterized by high cholesterol and triglycerides levels. Autosomal dominant hypercholesterolemia (ADH), due to the mutations in the LDLR, APOB, or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to the high levels of low-density lipoproteins (LDLs). We now report an exceptionally large family including 14 members with ADH. Through genome-wide mapping, analysis of regional/functional candidate genes, and whole exome sequencing, we identified a mutation in the APOE gene, c.500_502delTCC/p.Leu167del, previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia. We confirmed the involvement of the APOE p.Leu167del in ADH, with (1) a predicted destabilization of an alpha-helix in the binding domain, (2) a decreased apo E level in LDLs, and (3) a decreased catabolism of LDLs. Our results show that mutations in the APOE gene can be associated with bona fide ADH.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This paper reports an exceptionally large French family with autosomal dominant hypercholesterolemia (ADH) in which linkage mapping and exome sequencing identified the APOE p.Leu167del mutation as the likely cause. The authors conclude that APOE mutations can be associated with bona fide ADH and that APOE screening is warranted alongside LDLR, APOB, and PCSK9 in ADH molecular diagnosis.
Key findings
- In the HC126 family, genome-wide linkage gave a maximum LOD score of 2.55 (θ=0) at rs718087 on chromosome 19; multipoint analysis at 19q13.31–13.32 gave a maximum LOD score of 3.15 between rs1988065 and rs3513657 (19:43,374,601–45,439,163).
- The APOE c.500_502delTCC (p.Leu167del) mutation was identified and was not detected in over 220 controls. Additional APOE variants p.Arg269Gly and p.Arg235Trp were found in non-LDLR/APOB/PCSK9 probands and were absent in over 500 French controls.
- Two p.Leu167del carriers had total apo E levels of 4.09 mg/dL and 4.03 mg/dL, both within the normal range (2.30–6.30 mg/dL); apo E distribution showed a higher proportion in HDL (77% vs 63–69%) and a lower proportion in LDL (12% vs 18–25%).
- In one carrier after a 2-month washout, lipid values were triglycerides 3.7, total cholesterol 10.5, LDL-cholesterol 8.1, and HDL-cholesterol 0.7 mmol/L; LDL kinetics resembled those of familial hypercholesterolemia patients, with an increased LDL pool due to increased LDL production and decreased LDL catabolism. No splenomegaly or thrombocytopenia was present in the 12 APOE p.Leu167del carriers of HC126 nor in the proband of HC512.
Methods
- ADH families were recruited by the French National Research Network on Hypercholesterolemia; the HC126 family was initiated through proband II-2 and expanded to 27 individuals over 3 generations, exploring 23 meioses. Inclusion criteria included total and LDL-cholesterol above the 95th percentile, triglycerides below 1.5 mmol/L, and personal and/or documented familial xanthomas and/or early coronary artery disease.
- The study combined genome-wide linkage mapping (with 100,000 simulations; av.ELOD 2.1, max.ELOD 4.8), regional microsatellite/multipoint analysis, candidate gene sequencing, and whole exome sequencing in three affected members (III-2, III-7, III-8).
- APOE p.Leu167del was screened by direct fluorescent PCR in controls, and the APOE gene was sequenced in 153 non-LDLR/APOB/PCSK9 probands (55 French ADH and 98 Norwegian hyperlipidemics). The authors also performed homology modeling, measured apo E levels and lipoprotein distribution, and conducted in vivo apo B-100 kinetic studies in one patient after washout.
Limitations
- Stated: the apo E distribution data need confirmation because they are based on only two patients, including one under lipid-lowering therapy; the kinetic data need confirmation because they are based on only one patient.
- Stated: a LDL receptor-binding defect could not be directly excluded, and a prior in vitro competitive binding test with apo E from a heterozygous p.Leu167del carrier showed no significant binding defect, so the effect of the deleted mutant alone could not be observed.
- Evident: the small number of mutation carriers limits biochemical and kinetic conclusions; the family also includes possible phenocopies (I-3 and II-14) and an unclassified patient (II-5), suggesting another lipid abnormality in the family remains unidentified.
Model-written summary. Check it against the paper before relying on it.
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Verification
Claims the paper makes
4 of 27 cited sources checked · 1 supported · 1 flagged · accuracy not yet measured
At least one cited source doesn’t support this claim or points to a different paper, and none confirmed it — see the verdicts below.
In the paper
“Among 9 non-LDLR/-APOB/-PCSK9/-HCHOLA4 families we have identified, one was large enough to enable genome wide mapping of a new ADH gene (Marques-Pinheiro A et al. 2010).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Disputedcites Marques-Pinheiro A et al. 2010 sourceExperimental — accuracy not yet measured
The Abstract and Linkage analysis section distinguish the large family used to map HCHOLA4 from the nine families that excluded linkage to that locus. The paper therefore does not place the genome-mapped family among those nine; it says the opposite. Our copy provides no page numbers for these passages. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Disputed
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“at least 19% of ADH families in which the disease is not associated with a mutation within one of these three genes (Marduel M et al. 2010).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Partly supportedcites Marduel M et al. 2010 sourceExperimental — accuracy not yet measured
The Results and Discussion report that no mutation in LDLR, APOB or PCSK9 was identified in 258 of 1,358 French ADH probands (19.0%). This supports the percentage for that cohort, but the claim extends it to ADH families generally and treats an unidentified mutation as evidence that no mutation in those genes is associated with their disease. (LLM, conf=0.85)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Regional haplotype construction allowed the identification of a common region for affected members from D19S417 to D19S908 (Figure 1A).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Phenotypically unclassified patient II-5 did not carry the familial-disease haplotype”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Through genome wide mapping, analysis of regional/functional candidate genes and whole exome sequencing, we identified a mutation in the APOE gene, p.Leu167del”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a decreased catabolism of LDL”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The p.Leu167del variation interrupts one α helix in a group of four helices stabilized by a leucine zipper.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the c.500_502delTCC (p.Leu167del, formerly called Δ149Leu) variation in the APOE gene (RefSeq NM_000041.2) was found”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a decreased apo E level in LDL”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After this period, the lipid values for this patient were: 3.7, 10.5, 8.1 and 0.7 mmol/L for triglycerids, total-, LDL- and HDL-cholesterol respectively.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Strength:plain· not yet calibratedSingle caseTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- Probably not a substantial claim. 16
- It may state two separate claims as one. 24
- The quote only partly states this claim. 1
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“new ADH loci were recently mapped at 16q22.1, HCHOLA4 (Marques-Pinheiro A et al. 2010), and 8q24.22 (Cenarro A et al. 2011).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Supportedcites Marques-Pinheiro A et al. 2010 source
The Discussion states that a genome-wide scan in a large French family mapped a fourth ADH locus at 16q22.1. The Introduction names that locus HCHOLA4. The 8q24.22 locus is attributed to a different citation in the citing sentence, so it is not part of this verdict. (LLM, conf=0.94)
- Not checked — no full text of the sourcecites Cenarro A et al. 2011 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“VLDL and IDL kinetic parameters were in accordance with the high triglyceride level only observed for this measurement, and never before in this patient, showing similarities with a type III hyperlipoproteinemia (E2E2 genotype) such as the dramatically increased VLDL and IDL pool due to a decreased conversion rate (Ooi EM et al. 2010).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Partly supportedcites Ooi EM et al. 2010 sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Leu167 of apoE is not a conserved amino acid, but is the fourth residue in a 6 amino acid motif of which positions 1, 2, 3 and 6 are very well conserved from Xenopus tropicalis to Homo sapiens (Supp. Figure S3).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No splenomegaly or thrombocytopenia were present in the 12 APOE p.Leu167del carriers of the HC126 family nor in the proband of HC512 indicating that these subjects did not present the sea-blue histiocytosis disease.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The APOE p.Leu167del was not detected in over 220 controls, in agreement with Faivre et al. who had investigated 50 French controls, and indicating that this apo E variation is not a frequent polymorphism.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Faivre L et al. 2005 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The two first variants were shown to be frequent genomic variants (//snp.gs.washington.edu/EVS/, //www.1000genomes.org), excluding them from being a possible disease-causing mutation.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The recruitment of the HC126 family was initiated through the female proband II-2, and expanded to 27 individuals over 3 generations, thus exploring 23 meioses (Figure 1A).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Interestingly, the increased VLDL and IDL pool for the HC126 patient was also due to an increased production rate, that was not observed for E2E2 patients, but already reported for patients carrying a PCSK9 gene mutation (Ouguerram K et al. 2003).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Ouguerram K et al. 2003 source
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Apo E distribution in each lipoprotein fraction showed a higher proportion in HDL (77% vs 63–69%), and a lower proportion in LDL (12% vs 18–25%) (Supp. Table S3).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LDL kinetic parameters were similar to those from FH patients (mutation in the LDLR gene) with an increased LDL pool, which was the consequence of both an increase in LDL production rate and a decrease in LDL catabolism (Table 1).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The CEACAM8 variant is rare, 3/10755 in the Exome Variant Server and not reported by the “1000 genome” project.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“rare apo E mutants have been described associated with type III hyperlipoproteinemia or lipoprotein glomerulopathy (OMIM +611771).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not matchedcites OMIM +611771
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“previously reported associated with sea-blue histiocytosis and familial combined hyperlipidemia”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Apo E2 isoform is associated with lower LDL cholesterol, except for 5% of E2/E2 carriers who develop type III hyperlipoproteinemia (OMIM +107741)”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not matchedcites OMIM +107741
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Not matched
In the paper
“ADH is genetically heterogeneous and associated with mutations in the well-known LDLR (low density lipoprotein receptor) (FH, OMIM #606945), APOB (apolipoprotein B-100) (FDB, OMIM # 144010) and PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9, Abifadel M et al. 2003) genes.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Abifadel M et al. 2003 source
Strength:boosted· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Accordingly, IDL production is increased and, combined to the low IDL catabolism, leads to an increased LDL production.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The APOE p.Leu167del mutation was reported in subjects with familial combined hyperlipidemia (FCHL, type III dyslipoproteinemia) (Solanas-Barca M et al. 2012) and in the HC126 family reported here with a bona fide ADH.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Solanas-Barca M et al. 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Apo E4 isoform is associated with elevated total and LDL-cholesterol levels, due to the higher affinity of apo E4 for VLDL and LDL”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Hatters DM et al. 2006 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“a few rare apo E variants (p.Glu21Lys, p.Pro102Arg and, p.Leu270Glu) have been observed in probands with hyperLDLemia (type IIa hyperlipoproteinemia), but none co-segregated with hyperLDLemia in the families (Wardell MR et al. 1991, van den Maagdenberg AM et al. 1993).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Wardell MR et al. 1991 source
- Not checked — no full text of the sourcecites van den Maagdenberg AM et al. 1993
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these data need to be confirmed because they are based on the study of only two patients, including one under a lipid lowering therapy.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The other mutations, p.Arg235Trp and p.Arg269Gly, are at the origin of a loss of charge in the first and second α helices of the C-terminal domain that very probably change each helix’s properties, interaction with lipoproteins, and receptor binding.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“However, these data need to be confirmed because they are based on the study of only one patient.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“The p.Arg269Gly apo E mutant has been previously reported in a proband with type IIb hyperlipoproteinemia, differing from ADH by elevated plasma triglyceride levels (Wardell MR et al. 1991).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Wardell MR et al. 1991 source
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Whereas apo E3 and apo E4 bind with similarly high affinity to the LDL receptor, the binding of apo E2 is 50- to 100- times weaker (Weisgraber KH et al. 1982).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Weisgraber KH et al. 1982 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“as well as the two affected members I-3 and II-14 who highly probably display a phenocopy form of ADH”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
In the paper
“The APOE gene accounts for a significant fraction of the variation in plasma cholesterol levels (Eichner JE et al. 2002).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Eichner JE et al. 2002 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Altogether, both hypotheses are in agreement with a decreased catabolism of LDL bearing apo E p.Leu167del and thus explaining the hyperLDLemia observed in the family.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mutations in the LDLR or APOE gene may amplify the effect of these factors, and thus, according to the number or the nature of these factors, could be associated with an overlapping phenotype between FCHL and ADH.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LDL kinetic parameters of apo E mutant carrier were similar to those from FH patients strengthening the very probable effect of LDL bearing an apo E mutant on their catabolism.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Autosomal Dominant Hypercholesterolemia (ADH), due to mutations in the LDLR, APOB or PCSK9 genes, is characterized by an isolated elevation of cholesterol due to high levels of low-density lipoproteins (LDL).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Abifadel M et al. 2003 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“The APOE p.Leu167del mutation was reported to be associated with sea-blue histiocytosis (OMIM #26960)”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not matchedcites OMIM #26960
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The electrostatic surface charges are altered in apo E p.Leu167del, that also likely influences interaction with lipids and affinity of apo E to its receptors.”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The APOE p.Leu167del mutation was also reported in subjects with familial combined hyperlipidemia (FCHL, type III dyslipoproteinemia) (Solanas-Barca M et al. 2012).”
§ Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation > Abstract
What the sources say
- Not checked — no full text of the sourcecites Solanas-Barca M et al. 2012 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The authors state this as an assumption.
A compensatory increased activity of the normal apoE in the presence of the deleted mutant could mask a LDL receptor-binding defect.
“under the hypothesis of a compensatory increased activity of the normal apoE in the presence of the deleted mutant”
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“FH due to APOE deficiency is recessively inherited, as in APOE-deficient homozygotes, but APOE variants diagnosed as ADH have also been reported29).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Subsequently, whole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH29, 57, 118).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Within a Norwegian hyperlipidemic cohort, APOE p.Arg235Trp (Arg217Trp) was found in a 56-year-old man with total cholesterol, triglyceride, LDL, and HDL levels of 363, 239, 247, and 69.6 mg/dL, respectively, along with the apoE3/E4 isoforms29).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Of the 11 cases of APOE deficiency with reported mutation sites, four were homozygotes and seven were compound heterozygotes or heterozygotes27, 29-40).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [29]
Experimental — accuracy not yet measured
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.
Cenarro study is cited with two different years
MinorThe text cites the 8q24.22 locus study as published in 2011, but the matching reference lists its publication year as 2010.
“8q24.22 (Cenarro A et al. 2011)”
“4. Cenarro A Garcia-Otin AL Tejedor MT Solanas M Jarauta E Junquera C Ros E Mozas P Puzo J Pocovi M Civeira F 2010 A presumptive new locus for autosomal dominant hypercholesterolemia mapping to 8q24.22 Clin Genet 20629670”
Citations
Cites
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
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Self-citationThe Metabolic Basis of Inherited Diseases
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Apolipoprotein E structure: insights into function
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“Apo E distribution in each lipoprotein fraction showed a higher proportion in HDLs (77% vs. 63%– 69”
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Marduel, M., Carrié, A., Sassolas, A., Devillers, M., Carreau, V., Di Filippo, M., Erlich, D., Abifadel, M., Marques-Pinheiro, A., Munnich, A., et al. (2010) · Human Mutation · doi:10.1002/humu.21348 · Cited by 115
Self-citationCiveira, F., Jarauta, E., Cenarro, A., García-Otín, A. L., Tejedor, D., Zambón, D., Mallén, M., Ros, E., & Pocovı́, M. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.06.050 · Cited by 84
Solanas-Barca, M., de Castro-Orós, I., Mateo-Gallego, R., Cofán, M., Plana, N., Puzo, J., Burillo, E., Martín-Fuentes, P., Ros, E., Masana, L., et al. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.03.011 · Cited by 74
Flagged first, then by citations
Research works printed but not linked: 1
- Mahley, 1989, The metabolic basis of inherited diseases, 1195
Cited by
Sorted by citations
Items 101–132 of 132
Chora, J. R., Medeiros, A. M., Alves, A. C., & Bourbon, M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820519-8.00019-3 · Cited by 3
Genetic considerations in the treatment of familial hypercholesterolemia
Moyer, A. M., & Baudhuin, L. M. (2015) · Clinical Lipidology · doi:10.2217/clp.15.33 · Cited by 3
Epilepsy Combined With Multiple Gene Heterozygous Mutation
Qiuju, H., Zhuang, J., Qi, W., Li, Z., Wang, D., Sun, X., & Yingjun, X. (2022) · Frontiers in Pediatrics · doi:10.3389/fped.2022.763642 · Cited by 2
Molecular diagnostics of familial hypercholesterolemia in Russia: yesterday, today and tomorrow
Zakharova, F. M., Мандельштам, М. Ю., Bogoslovskaya, T. Y., & Vasiliev, V. B. (2024) · Medical academic journal · doi:10.17816/maj630505 · Cited by 2
Azar, Y., Ludwig, T. E., Bon, H. L., Strøm, T. B., Bluteau, O., Filippo, M. D., Carrié, A., Chtioui, H., Béliard, S., Marmontel, O., et al. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.118596 · Cited by 2
Self-citationAPOE p.(Leu167del) variant in hypercholesterolemia: Prevalence & phenotypic expression
Bello-Álvarez, D., Cenarro, A., Bea, A. M., Marco-Benedí, V., Jarauta, E., Ortiz-Palma, P., Ortega, E., González-Lleó, A. M., & Civeira, F. (2025) · Journal of clinical lipidology · doi:10.1016/j.jacl.2025.09.016 · Cited by 2
Noorian, S., Razmandeh, R., & Jazayeri, R. (2022) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-022-01007-1 · Cited by 2
Gratton, J., Humphries, S. E., Schmidt, A. F., Patel, R. S., Sofat, R., Finan, C., Morris, J. K., Hingorani, A. D., & Futema, M. (2023) · BMJ Public Health · doi:10.1136/bmjph-2023-000021 · Cited by 2
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The Spectrum of Genetic Causes of Familial Hypercholesterolemia Phenotype
Bourbon, M., Alves, A. C., Chora, J. R., Hooper, A. J., & Abifadel, M. (2026) · Current Atherosclerosis Reports · doi:10.1007/s11883-026-01435-x · Cited by 1
Self-citationGenetic screening to improve the diagnosis of familial hypercholesterolemia
Faiz, F., Nguyen, L., BOCKXMEER, F. M. V., & Hooper, A. J. (2014) · Clinical Lipidology · doi:10.2217/clp.14.32 · Cited by 1
Progress in genetics of plasma lipids
Hegele, R. A. (2014) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000063 · Cited by 1
Rare monogenic disorders of cholesterol metabolism
Bednarska‐Makaruk, M., & Ługowska, A. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85857-1.00024-9 · Cited by 2
In silico prediction of blood cholesterol levels from genotype data
Reggiani, F., Carraro, M., Belligoli, A., Sanna, M., Prà, C. D., Favaretto, F., Ferrari, C., Vettor, R., & Tosatto, S. C. E. (2020) · PLoS ONE · doi:10.1371/journal.pone.0227191 · Cited by 1
Molecular investigation of familial hypercholesterolaemia: from gene to genome
Faiz, F. (2014) · UWA Profiles and Research Repository (University of Western Australia)
Resolving the Genetic Etiology of Hypercholesterolemia in Familial Combined Hyperlipidemia
Bamimore, M. A. (2013) · Scholarship@Western (Western University)
Awan, Z. A., DELVIN, E. E., Levy, E. H., Genest, J. J., Davignon, J., Seidah, N. G., & Baass, A. W. (2013)
Clinical Applications for Next Generation Sequencing in Cardiology
Ponińska, J. K., Płoski, R., & Bilińska, Z. T. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-801739-5.00010-6
Monogenic Hypercholesterolemias
Civeira, F., & Pocovı́, M. (2015) · Contemporary Endocrinology · doi:10.1007/978-1-60761-424-1_10
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Тимощенко, О. В., & Шахтшнейдер, Е. В. (2024) · Russian Journal of Cardiology · doi:10.15829/1560-4071-2024-5874
Pshenichnikova, I. I., Владиславович, Е. М., Pupykina, V. V., Osmanov, I. M., Lavrova, T. N., Tebenkova, T. A., Varakina, E. E., Kuznetsova, A. O., Николаевна, Б. С., Miroshina, A., et al. (2025) · Meditsinskiy sovet = Medical Council · doi:10.21518/ms2025-353
Genetic causes of lipid profile variability in familial hypercholesterolemia
Mikhailina, V. I., Zaicenoka, M., Kiseleva, A. V., Н., М. А., & М., Д. О. (2026) · CARDIOVASCULAR THERAPY AND PREVENTION · doi:10.15829/1728-8800-2025-4607 · Cited by 1
Hypercholestérolémie familiale : recherche de nouveaux gènes et étude des formes polygéniques
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Approches biochimique, épidémiologique et clinique du métabolisme intégré de la Lipoprotéine (a)
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Bararu‐Bojan, I., Vladeanu, M. C., Iliescu-Halițchi, D., Pleșoianu, C. E., Bojan, A., Frăsinariu, O. E., Tudor, R. C., Ciocoiu, M., Tudor, C., Haliţchi, C. I., et al. (2026) · Diagnostics · doi:10.3390/diagnostics16152313
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Metadata
- Authors
- Marduel, M., Ouguerram, K., Serre, V., Bonnefont-Rousselot, D., Marques-Pinheiro, A., Erik Berge, K., Devillers, M., Luc, G., Lecerf, J.-M., Tosolini, L., Erlich, D., Peloso, G. M., Stitziel, N., Nitchké, P., Jaïs, J.-P., The French Research Network on ADH, Abifadel, M., Kathiresan, S., Leren, T. P., Rabès, J.-P., Boileau, C., & Varret, M.
- Affiliations
- Inserm (FR)
- Medical Genetics Laboratory; Oslo University Hospital Rikshospitalet; Oslo; Norway
- Université de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Université Paris Denis Diderot; Paris; France
- Broad Institute (US)
- Hôpital Necker-Enfants Malades (FR)
- Oslo University Hospital (NO)
- Corresponding author
- Varret, Mathilde
- ORCID
- Venue
- Human Mutation
- Publisher
- Wiley
- Published
- 2012-10-11
- Volume
- 34
- Issue
- 1
- Pages
- 83-87
- ISSN
- 1059-7794 (ISSN-L)
- PMC
- PMC3638718
- OpenAlex
- W2072770085
- Semantic Scholar
- e4d31a1313c36bcd4d0998701fcdf0156fa0f973
- Cited by
- 133
- References
- 32
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 6 · 2019: 9 · 2018: 12 · 2017: 12 · 2016: 9 · 2015: 7 · 2014: 14 · 2013: 10 · 2012: 1
- FWCI
- 10.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-05-PCOD-0017, ANR-08-GENO-0002, ANR-06-MRAR-0038)
- National Heart, Lung, and Blood Institute (R01HL107816)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- autosomal dominant hypercholesterolemia, apolipoprotein E, familial hypercholesterolemia, LDL receptor, apolipoprotein B, PCSK9, type III hyperlipoproteinemia, LDL catabolism, family studies, exome sequencing, genome-wide mapping
- MeSH terms
- Adolescent, Adult, Apolipoproteins E, Child, Cholesterol, Chromosomes, Human, Pair 19, Family Health, Female, Haplotypes, Humans, Hyperlipoproteinemia Type II, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Models, Molecular, Mutation, Pedigree, Triglycerides, Gene Deletion, Protein Structure, Secondary, Protein Structure, Tertiary, Genetic Predisposition to Disease, Young Adult
About these checks
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.
A language model drew the claims from the paper on 2026-10-31, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-31 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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