- 作者：Zuhier Awan ; Hong Y. Choi ; Nathan Stitziel ; Isabelle Ruel ; Mary Aderayo Bamimore ; Regina Husa ; Marie-Helene Gagnon ; Rui-Hao L. Wang ; Gina M. Peloso ; Robert A. Hegele ; Nabil G. Seidah ; Sekar Kathiresan ; Jacques Genest
- 关键词：Autosomal dominant hypercholesterolemia ; Familial hypercholesterolemia ; APOE gene
- 刊名：Atherosclerosis
- 出版年：December, 2013
- 年：2013
- 卷：231
- 期：2
- 页码：218-222
- 全文大小：1279 K
Background
Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the low density lipoprotein receptor (LDLR), its ligand apoB (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Yet DNA sequencing does not identify mutations in these genes in a significant number of cases, suggesting that ADH has multiple genetic etiologies.Methods
Through a combination of clinical examination, biochemical analysis, candidate gene approach and next-generation exome sequencing we investigated the genetic basis of an ADH phenotype in a proband of an Italian origin.
Results
The proband presented with an acute myocardial infarction at age 43. He had tendinous xanthomas, xanthelasmas and elevated levels of total and LDL cholesterol, at 11.2 and 9.69聽mmol/L, respectively, with normal levels of HDL cholesterol and triglycerides at 1.62 and 1.13聽mmol/L, respectively. HPLC lipoprotein profile showed selective increase in LDL-C. DNA sequencing did not identify any mutation in the LDLR, PCSK9, LDLRAP1 and APOB gene. We then performed exome sequencing on three individuals from the family. The strongest evidence of association was found for the previously identified apolipoprotein E mutation (APOE, chromosome 19:45412053-55) known as APOE Leu167del, an in-frame three base-pair deletion. Computational biology confirmed the deleterious nature of this mutation. The Leu167del mutation is predicted to alter the protein structure of apoE near the 伪-helix within the receptor binding domain.
Conclusions
This report confirms a previous report that ADH can be caused by mutations within the APOE gene and represents the 4th loci causing ADH. Standard screening for ADH should include APOE gene.