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

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...

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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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2275 1539-7262
DOI:	10.1194/jlr.P055699