title: Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France.
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.
authors.affiliation: Faculty of Pharmacy (CP206/04), Université Libre de Bruxelles, B-1050 Brussels, Belgium.
authors.forename: René
authors.initials: R
authors.lastname: Wintjens
authors.affiliation: Centre de Biologie et de Pathologie Est, CHU Lyon, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bozon
authors.affiliation: Laboratoire Commun de Biologie et Génétiques Moléculaires (LCBGM), AP-HP (Assistance Publique-Hopitaux de Paris), Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Khaldia
authors.initials: K
authors.lastname: Belabbas
authors.affiliation: Service d'Endocrinologie, CHU du Lamentin, F-97232 Le Lamentin, Martinique, France.
authors.forename: Félicien
authors.initials: F
authors.lastname: MBou
authors.affiliation: Service de Gastroentérologie et Nutrition Pédiatrique, AP-HP, Hôpital Trousseau, F-75012, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Girardet
authors.affiliation: Service de Gastroentérologie et Nutrition Pédiatrique, AP-HP, Hôpital Trousseau, F-75012, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tounian
authors.affiliation: Service d'Endocrinologie, Diabétologie et Nutrition, CH Angers, F-49933, Angers, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Jolly
authors.affiliation: Service d'Endocrinologie, Diabétologie et Nutrition, CH Angers, F-49933, Angers, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Boccara
authors.affiliation: Service d'Endocrinologie, Diabétologie et Nutrition, CH Angers, F-49933, Angers, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Service de Gastroentérologie et Nutrition Pédiatrique, AP-HP, Hôpital Trousseau, F-75012, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Karsenty
authors.affiliation: Service de Gastroentérologie et Nutrition Pédiatrique, AP-HP, Hôpital Trousseau, F-75012, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Dubern
authors.affiliation: 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.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Carel
authors.affiliation: 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.
authors.forename: Ahlam
authors.initials: A
authors.lastname: Azar-Kolakez
authors.affiliation: 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.
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.affiliation: Service de médecine pédiatrique, Hopital Clocheville, CHU Tours, F-37044, Tours, France.
authors.forename: François
authors.initials: F
authors.lastname: Labarthe
authors.affiliation: Service de pédiatrie générale, Centre Hospitalier d'Argenteuil, F-95107, Argenteuil, France.
authors.forename: Anne-Marie Colin
authors.initials: AM
authors.lastname: Gorsky
authors.affiliation: Service de Cardiologie, CHU Bordeaux-Haut Lévêque, F-33604, Pessac, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Horovitz
authors.affiliation: Service de Maternité, CH Hagueneau, F-67504 Hagueneau, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Tamarindi
authors.affiliation: Service de Médecine Interne, CH Mulhouse, Hôpital E. Muller, F-68070 Mulhouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Kieffer
authors.affiliation: Service de Pédiatrie Médicale, CH Limoges, Hôpital mère/enfants, F-87042 Limoges, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Lienhardt
authors.affiliation: Laboratoire Commun de Biologie et Génétiques Moléculaires (LCBGM), AP-HP (Assistance Publique-Hopitaux de Paris), Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lascols
authors.affiliation: Centre de Biologie et de Pathologie Est, CHU Lyon, France Service de Pédiatrie Médicale, CH Limoges, Hôpital mère/enfants, F-87042 Limoges, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Di Filippo
authors.affiliation: 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.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Dufernez
mesh_terms: D000328:Adult; D001055:Apolipoproteins B / Q000737:chemistry / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002648:Child; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005602:France; D060005:Genotyping Techniques; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D000071449:Proprotein Convertase 9 / Q000235:genetics; D000072756:Protein Conformation, alpha-Helical; D011973:Receptors, LDL / Q000235:genetics; D055815:Young Adult
chemical_list: D001055:Apolipoproteins B; D001057:Apolipoproteins E; C573412:LDLR protein, human; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: apolipoprotein E; apolipoproteins; cholesterol; familial hypercholesterolemia; low density lipoprotein; phenotype/genotype correlation