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J Lipid Res. 2016 Mar;57(3):482-91. doi: 10.1194/jlr.P055699. Epub 2016 Jan 22.

Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.

Author information

1
Faculty of Pharmacy (CP206/04), Université Libre de Bruxelles, B-1050 Brussels, Belgium.
2
Centre de Biologie et de Pathologie Est, CHU Lyon, France.
3
Laboratoire Commun de Biologie et Génétiques Moléculaires (LCBGM), AP-HP (Assistance Publique-Hopitaux de Paris), Hôpital Saint-Antoine, F-75012, Paris, France.
4
Service d'Endocrinologie, CHU du Lamentin, F-97232 Le Lamentin, Martinique, France.
5
Service de Gastroentérologie et Nutrition Pédiatrique, AP-HP, Hôpital Trousseau, F-75012, Paris, France.
6
Service d'Endocrinologie, Diabétologie et Nutrition, CH Angers, F-49933, Angers, France.
7
Université Paris Diderot, Sorbonne Paris Cité, F-75019, Paris, France Service d'Endocrinologie Diabétologie Pédiatrique et Centre de Référence des Maladies Endocriniennes Rares de la Croissance, AP-HP, Hôpital Robert Debré, F-75019, Paris, France.
8
Service de Médecine Infantile et de génétique clinique, CHU Nancy-Brabois, F-54511 Vandoeuvre les Nancy, France INSERM NGERE UMR 954, F-54500, Vandoeuvre les Nancy, France.
9
Service de médecine pédiatrique, Hopital Clocheville, CHU Tours, F-37044, Tours, France.
10
Service de pédiatrie générale, Centre Hospitalier d'Argenteuil, F-95107, Argenteuil, France.
11
Service de Cardiologie, CHU Bordeaux-Haut Lévêque, F-33604, Pessac, France.
12
Service de Maternité, CH Hagueneau, F-67504 Hagueneau, France.
13
Service de Médecine Interne, CH Mulhouse, Hôpital E. Muller, F-68070 Mulhouse, France.
14
Service de Pédiatrie Médicale, CH Limoges, Hôpital mère/enfants, F-87042 Limoges, France.
15
Centre de Biologie et de Pathologie Est, CHU Lyon, France Service de Pédiatrie Médicale, CH Limoges, Hôpital mère/enfants, F-87042 Limoges, France.
16
Laboratoire Commun de Biologie et Génétiques Moléculaires (LCBGM), AP-HP (Assistance Publique-Hopitaux de Paris), Hôpital Saint-Antoine, F-75012, Paris, France fabienne.dufernez@sat.aphp.fr.

Abstract

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.

KEYWORDS:

apolipoprotein E; apolipoproteins; cholesterol; familial hypercholesterolemia; low density lipoprotein; phenotype/genotype correlation

PMID:
26802169
PMCID:
PMC4766997
[Available on 2017-03-01]
DOI:
10.1194/jlr.P055699
[Indexed for MEDLINE]
Free PMC Article

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