Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France[S]

• Published in: Journal of lipid research Vol. 57; no. 3; pp. 482 - 491
• Main Authors: Wintjens, René, Bozon, Dominique, Belabbas, Khaldia, MBou, Félicien, Girardet, Jean-Philippe, Tounian, Patrick, Jolly, Mathilde, Boccara, Franck, Cohen, Ariel, Karsenty, Alexandra, Dubern, Béatrice, Carel, Jean-Claude, Azar-Kolakez, Ahlam, Feillet, François, Labarthe, François, Gorsky, Anne-Marie Colin, Horovitz, Alice, Tamarindi, Catherine, Kieffer, Pierre, Lienhardt, Anne, Lascols, Olivier, Di Filippo, Mathilde, Dufernez, Fabienne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2016; American Society for Biochemistry and Molecular Biology; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Adult; apolipoprotein E; apolipoproteins; Apolipoproteins B - chemistry; Apolipoproteins B - genetics; Apolipoproteins E - genetics; Child; cholesterol; Cohort Studies; Endocrinology and metabolism; Exons - genetics; familial hypercholesterolemia; Female; France; Genetics; Genotyping Techniques; Human genetics; Human health and pathology; Humans; Hyperlipoproteinemia Type II - diagnosis; Hyperlipoproteinemia Type II - genetics; Life Sciences; low density lipoprotein; Male; Models, Molecular; Mutation; Patient-Oriented and Epidemiological Research; Phenotype; phenotype/genotype correlation; Proprotein Convertase 9 - genetics; Protein Conformation, alpha-Helical; Receptors, LDL - genetics; Young Adult; apolipoprotein E; cholesterol; apolipoproteins; low density lipoprotein; phenotype/genotype correlation; familial hypercholesterolemia
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.P055699

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.