Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France
Open accessAbstract
Autosomal dominant hypercholesterolemia (ADH) is a human disorder characterized phenotypically by isolated high-cholesterol levels. Mutations in the low density lipoprotein receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes are well known to be associated with the disease. To characterize the genetic background associated with ADH in France, the three ADH-associated genes were sequenced in a cohort of 120 children and 109 adult patients. Fifty-one percent of the cohort had a possible deleterious variant in LDLR, 3.1% in APOB, and 1.7% in PCSK9. We identified 18 new variants in LDLR and 2 in PCSK9. Three LDLR variants, including two newly identified, were studied by minigene reporter assay confirming the predicted effects on splicing. Additionally, as recently an in-frame deletion in the APOE gene was found to be linked to ADH, the sequencing of this latter gene was performed in patients without a deleterious variant in the three former genes. An APOE variant was identified in three patients with isolated severe hypercholesterolemia giving a frequency of 1.3% in the cohort. Therefore, even though LDLR mutations are the major cause of ADH with a large mutation spectrum, APOE variants were found to be significantly associated with the disease. Furthermore, using structural analysis and modeling, the identified APOE sequence changes were predicted to impact protein function.
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Three carriers of the rare p.Gly145Asp variant had the ε2ε2 genotype, forming the rare ε2ε1 genotype.
“In our study, three carriers of the rare p.Gly145Asp variant had the ε2ε2 (homozygous for the common p.Arg176Cys variant), forming the rare ε2ε1 genotype [32,33,34,35,36].”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [35]
The APOE variants and structural analysis section (p. 487) identifies a patient with p.(Gly145Asp) and the E2E2 genotype, supporting that association. It does not describe this combination as the rare ε2ε1 genotype. The citing sentence’s three carriers are explicitly from the citing authors’ own study, not a count attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPOE (Arg145Cys) homozygote was also found in a cohort of autosomal dominant hypercholesterolemia (ADH) patients in France.
“APOE (Arg145Cys) homozygote was also found in a cohort of autosomal dominant hypercholesterolemia (ADH) patients in France57).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [57]
The Patients section describes a French ADH cohort, and Table 2 and the discussion (p. 489) report a patient homozygous for an APOE variant. The paper names that variant p.(Arg163Cys), not Arg145Cys; our copy does not establish whether those labels are equivalent. (LLM, conf=0.83)
Experimental — accuracy not yet measuredWhole-exome sequencing and functional analysis of large French and Italian families containing many FH patients revealed that APOE p.Leu167del (Leu149del) is involved in ADH.
“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 [57]
The APOE variants and structural analysis section (p. 487) identifies p.Leu167del in a French patient with probable ADH, and the discussion (p. 489) says it is thought to contribute to the ADH phenotype. But this paper studied a French cohort using targeted Sanger sequencing and in silico analysis, not whole-exome sequencing and functional analysis of large French and Italian families; it says the variant’s binding defect was not demonstrated. (LLM, conf=0.91)
Experimental — accuracy not yet measuredBased on previous research, the ε2ε1 genotype is considered likely pathogenic for FD.
“Based on previous research data [32,33,34,35,36], we considered the ε2ε1 genotype as likely pathogenic for FD.”
From Spectrum and Prevalence of Rare APOE Variants and Their Association with Familial Dysbetalipoproteinemia (2024) · cites this paper as [35]
The APOE variants and structural analysis section (p. 487) discusses an E2E2 patient with mixed dyslipidemia, and Table 2 (p. 489) lists E2E2, but neither addresses ε2ε1. Searches for ε2ε1, E2E1, and the E1 isoform found no passage assessing whether ε2ε1 is likely pathogenic for FD. (LLM, conf=0.75)
Experimental — accuracy not yet measuredThe Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys).
“The Gly127Asp variant is in linkage disequilibrium with APOE2 (Arg158Cys) and was detected as APOE1 (Gly127Asp, Arg158Cys)26, 38, 56, 57).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [57]
The APOE variants and structural analysis section (p. 487) lists Gly145Asp, not Gly127Asp, among the variants studied. A later discussion (p. 489) associates Gly145Asp with an E2E2 genotype. Searches for Gly127Asp, Arg158Cys, APOE1, and linkage disequilibrium found no passage addressing the claimed combination. (LLM, conf=0.74)
Experimental — accuracy not yet measured
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Cites
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- Authors
- Wintjens, R., Bozon, D., Belabbas, K., MBou, F., Girardet, J.-P., Tounian, P., Jolly, M., Boccara, F., Cohen, A., Karsenty, A., Dubern, B., Carel, J.-C., Azar-Kolakez, A., Feillet, F., Labarthe, F., Gorsky, A.-M. C., Horovitz, A., Tamarindi, C., Kieffer, P., Lienhardt, A., Lascols, O., Di Filippo, M., & Dufernez, F.
- Affiliations
- Université Libre de Bruxelles (BE)
- Hospices Civils de Lyon (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Centre Hospitalier Universitaire de Martinique (MQ)
- Hôpital Armand-Trousseau (FR)
- Centre Hospitalier Universitaire d'Angers (FR)
- Sorbonne Paris Cité (FR)
- Inserm (FR)
- Centre Hospitalier Universitaire de Tours (FR)
- Centre Hospitalier Victor Dupouy (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Centre Hospitalier de Mulhouse (FR)
- Centre Hospitalier Universitaire de Limoges (FR)
- Corresponding author
- Dufernez, Fabienne
- ORCID
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 57
- Issue
- 3
- Pages
- 482-491
- ISSN
- 0022-2275 (ISSN-L)
- PMC
- PMC4766997
- OpenAlex
- W2290877385
- Cited by
- 47
- References
- 5
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 3 · 2023: 5 · 2022: 6 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 1
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Assistance publique-Hôpitaux de Paris
- 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
- autosomal dominant hypercholesterolemia, LDLR mutations, apolipoprotein B, PCSK9, in-frame deletion, genetic variants, protein structure modeling, French patients
- MeSH terms
- Proprotein Convertase 9, Protein Conformation, alpha-Helical, Adult, Apolipoproteins B, Apolipoproteins E, Child, Exons, Female, France, Humans, Hyperlipoproteinemia Type II, Male, Models, Molecular, Mutation, Phenotype, Receptors, LDL, Cohort Studies, Young Adult, Genotyping Techniques
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