The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes

Cenarro, Ana; Etxebarria, Aitor; de Castro-Orós, Isabel; Stef, Marianne; Bea, Ana M.; Palacios, Lourdes; Mateo-Gallego, Rocío; Benito-Vicente, Asier; Ostolaza, Helena; Tejedor, Teresa; Martín, César; Civeira, Fernando

doi:10.1210/jc.2015-3874

Cited by 100Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes

Cenarro, Ana, Etxebarria, Aitor, de Castro-Orós, Isabel, Stef, Marianne, Bea, Ana M., Palacios, Lourdes, Mateo-Gallego, Rocío, Benito-Vicente, Asier +4 more·2016·The Journal of Clinical Endocrinology & Metabolism

DOI 10.1210/jc.2015-3874

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Abstract

Context: The p.Leu167del mutation in the APOE gene has been associated with hyperlipidemia. Objectives: Our objective was to determine the frequency of p.Leu167del mutation in APOE gene in subjects with autosomal dominant hypercholesterolemia (ADH) in whom LDLR, APOB, and PCSK9 mutations had been excluded and to identify the mechanisms by which this mutant apo E causes hypercholesterolemia. Design: The APOE gene was analyzed in a case-control study. Setting: The study was conducted at a University Hospital Lipid Clinic. Patients or Other Participants: Two groups (ADH, 288 patients; control, 220 normolipidemic subjects) were included. Intervention: We performed sequencing of APOE gene and proteomic and cellular experiments. Main Outcome Measure: To determine the frequency of the p.Leu167del mutation and the mechanism by which it causes hypercholesterolemia. Results: In the ADH group, nine subjects (3.1%) were carriers of the APOE c.500_502delTCC, p.Leu167del mutation, cosegregating with hypercholesterolemia in studied families. Proteomic quantification of wild-type and mutant apo E in very low-density lipoprotein (VLDL) from carrier subjects revealed that apo E3 is almost a 5-fold increase compared to mutant apo E. Cultured cell studies revealed that VLDL from mutation carriers had a significantly higher uptake by HepG2 and THP-1 cells compared to VLDL from subjects with E3/E3 or E2/E2 genotypes. Transcriptional down-regulation of LDLR was also confirmed. Conclusions: p.Leu167del mutation in APOE gene is the cause of hypercholesterolemia in the 3.1% of our ADH subjects without LDLR, APOB, and PCSK9 mutations. The mechanism by which this mutation is associated to ADH is that VLDL carrying the mutant apo E produces LDLR down-regulation, thereby raising plasma low-density lipoprotein cholesterol levels.

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Abstract 13801: The p.Leu167del Mutation in APOE Gene causes Autosomal Dominant Hypercholesterolemia by Down-Regulation of LDL Receptor Expression in Hepatocytes
Cenarro, A., Martı́n, C., Stef, M. A., de Castro-Orós, I., Etxebarria, A., Palacios, L., Mateo‐Gállego, R., Ostolaza, H., Tejedor, M. T., & Civeira, F. (2014) · Circulation · doi:10.1161/circ.130.suppl_2.13801
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APOE p.Leu167del mutation in familial hypercholesterolemia
Awan, Z. A., Choi, H. Y., Stitziel, N. O., Ruel, I. L., Bamimore, M. A., Husa, R., Gagnon, M.-H., Wang, R.-H. L., Peloso, G. M., Hegele, R. A., et al. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.09.007 · Cited by 104 · see citing works
Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with theAPOEp.Leu167del Mutation
Marduel, M., Ouguerram, K., Serre, V., Bonnefont-Rousselot, D., Marques-Pinheiro, A., Erik Berge, K., Devillers, M., Luc, G., Lecerf, J.-M., Tosolini, L., et al. (2013) · Human Mutation · doi:10.1002/humu.22215 · Cited by 133 · see citing works
Abstract 5: A Novel APOE p.Leu166del Mutation in Autosomal Dominant Familial Hypercholesterolemia
Awan, Z. A., Choi, H. Y., Stitziel, N. O., Ruel, I. L., Husa, R., Gagnon, M.-H., Wang, R. H., Katherisan, S., Seidah, N. G., & Genest, J. J. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvb.33.suppl_1.a5

Authors: Cenarro, A., Etxebarria, A., de Castro-Orós, I., Stef, M., Bea, A. M., Palacios, L., Mateo-Gallego, R., Benito-Vicente, A., Ostolaza, H., Tejedor, T., Martín, C., & Civeira, F.
Affiliations: Hospital Universitario Miguel Servet (ES)
Consejo Superior de Investigaciones Científicas (ES)
Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis (A.C., I.d.C.-O., A.M.B., R.M.-G., F.C.), Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón, Zaragoza, Spain
Grifols (Spain) (ES)
Unidad de Biofísica (Consejo Superior de Investigaciones Científicas, Universidad del País Vasco/Euskal Herriko Unibertsitatea) and Departamento de Bioquímica y Biología Molecular (A.E., A.B.-V., H.O., C.M.), Universidad del País Vasco/Euskal Herriko Unibertsitatea, Bilbao, Spain
Departamento de Anatomía (T.T.), Embriología y Genética, Universidad de Zaragoza, Spain
Corresponding author: Cenarro, Ana
ORCID: Cenarro, Ana
Stef, Marianne
Bea, Ana M.
Ostolaza, Helena
Civeira, Fernando
Venue: The Journal of Clinical Endocrinology & Metabolism
Publisher: The Endocrine Society
Published: 2016-05-01
Volume: 101
Issue: 5
Pages: 2113-2121
ISSN: 0021-972X (ISSN-L)
1945-7197
DOI: 10.1210/jc.2015-3874
OpenAlex: W2312052109
Semantic Scholar: cd8a8694e4016d8d3a247efb869bfba0e8435ce6
Cited by: 100
References: 32
Citations by year: 2026: 7 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 14 · 2021: 15 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 13 · 2016: 4
FWCI: 11.43
Type: journal article
Language: en
Open access: closed
Locations: The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
PubMed (publishedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
Funders: Ministerio de Economía y Competitividad (PI12/)
Universidad de Zaragoza
Instituto de Salud Carlos III (PI12/01087, PI13/02507)
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, VLDL, LDL cholesterol elevation, hyperlipidemia, APOE genotype
MeSH terms: Adult, Apolipoproteins E, DNA Mutational Analysis, Female, Humans, Hyperlipoproteinemia Type II, Male, Middle Aged, Mutation, Receptors, LDL, Down-Regulation, Case-Control Studies, Hepatocytes

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The p.Leu167del Mutation in APOE Gene Causes Autosomal Dominant Hypercholesterolemia by Down-regulation of LDL Receptor Expression in Hepatocytes

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