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

作者：Wintjens Rene; Bozon Dominique; Belabbas Khaldia; MBou Felicien; Girardet Jean Philippe; Tounian Patrick; Jolly Mathilde; Boccara Franck; Cohen Ariel; Karsenty Alexandra; Dubern Beatrice; Carel Jean Claude; Azar Kolakez Ahlam; Feillet Francois; Labarthe Francois; Gorsky Anne Marie Colin; Horovitz Alice; Tamarindi Catherine; Kieffer Pierre; Lienhardt Anne; Lascols Olivier; Di Filippo Mathilde; Dufernez Fabienne

来源：The Journal of Lipid Research, 2016, 57(3): 482-491.

DOI：10.1194/jlr.P055699

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

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.

• 出版日期2016-3
• 单位河南工业大学