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

René Wintjens 1 Dominique Bozon 2 Khaldia Belabbas 3 Félicien Mbou 4 Jean-Philippe Girardet 5 Patrick Tounian 5 Mathilde Jolly 6 Franck Boccara 7 Ariel Cohen 7 Alexandra Karsenty 5 Beatrice Dubern 5 Jean-Claude Carel 8, 9 Ahlam Azar-Kolakez 8, 9 François Feillet 10, 11 François Labarthe 12, 13 Anne-Marie Colin Gorsky 14 Alice Horovitz 15 Catherine Tamarindi 16 Pierre Kieffer 17 Anne Lienhardt 18 Olivier Lascols 19, 3 Mathilde Di Filippo 20 Fabienne Dufernez 3, 5 
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.
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J. Lipid Res.-2016-Wintjens-48...
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René Wintjens, Dominique Bozon, Khaldia Belabbas, Félicien Mbou, Jean-Philippe Girardet, et al.. Global molecular analysis and APOE mutations in a cohort of autosomal dominant hypercholesterolemia patients in France. Journal of Lipid Research, American Society for Biochemistry and Molecular Biology, 2016, 57 (3), pp.482-491. ⟨10.1194/jlr.P055699⟩. ⟨hal-01662494⟩



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