Elsevier

Atherosclerosis

Volume 231, Issue 2, December 2013, Pages 218-222
Atherosclerosis

APOE p.Leu167del mutation in familial hypercholesterolemia

https://doi.org/10.1016/j.atherosclerosis.2013.09.007Get rights and content

Highlights

  • Candidate gene approach may fail to identify a significant number of ADH patients.

  • GWAS and next-generation exome sequencing has broadened the findings of contributing genes.

  • Standard screening for ADH should include APOE gene.

  • This may impact large registries of ADH and patients access to specialized medical care.

Abstract

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 mmol/L, respectively, with normal levels of HDL cholesterol and triglycerides at 1.62 and 1.13 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 α-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.

Introduction

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by cutaneous xanthomas and xanthelasmas, a marked increase in low density lipoprotein (LDL)-cholesterol (LDL-C) and premature coronary artery disease. The genetic basis of FH is primarily from mutations within the LDLR gene, coding for the LDL receptor (LDLR) [1], [2]. At least two other genes other than the LDLR have been found to cause a phenotype clinically similar to FH. These include the APOB [3] and PCSK9 [4], [5] genes. The term Autosomal Dominant Hypercholesterolemia (ADH) thus captures the genetic diversity of FH. Mutations in the LDLRAP1 [6], coding for the LDLR adaptor protein 1 cause the rare autosomal recessive hypercholesterolemia disorder. In population-based studies, ∼20% of patients with the FH phenotype do not have identifiable mutations in these genes [7]. Genome-wide association studies (GWAS) had broadened the search for genes contributing to LDL-C levels; this technique has allowed the identification of several genes that contribute to small variation in LDL-C levels [8]. Remarkably, mutations in several of the genes identified by GWAS have been previously identified in patients with FH. Contemporary techniques in high-throughput sequencing allow the sequencing of all exons expressed in the human genome. Using exome sequencing has allowed the identification of the genetic basis of rare diseases, usually of an extreme phenotype. Here, we present a mutation of the APOE gene in a kindred with a classical ADH phenotype.

ApoE is a multi-functional glycosylated protein (34 KDa) secreted from a variety of tissues, including the liver, brain, kidney, adrenals, adipocytes, macrophages and immune cells. It is a key component of all lipoproteins, but especially of triglyceride-rich lipoproteins (chylomicrons and chylomicron remnants), VLDL (very low density lipoproteins) and IDL (intermediate density lipoproteins), and participates in their catabolism through interacting with receptors belonging to the LDLR superfamily. ApoE is recognized by most receptors of this class, but especially the LDLR (also known as the apoB/E receptor), LDL-receptor related peptide-1 (LRP1) and LRP8 (apoE receptor 2) [9]. Three common polymorphisms at the APOE gene, apoE3, E4 and E2 have been recognized. ApoE2 binds with much less affinity to the LDLR. Homozygosity for the E2 allele is seen in approximately 0.5% of the population and a small percentage of these subjects will develop type III dyslipidemia, characterized by accumulation of remnant lipoprotein particles in plasma and premature vascular disease. A “second hit” is postulated to contribute to the expression of the apoE2/E2 genotype into a clinical dyslipidemia phenotype [10]. Rare mutations of APOE also lead to a rare form of lipid glomerulopathy [11]. Genome-wide association studies have shown that apoE is strongly associated with LDL-C levels [8]. Marduel et al. [12] were the first to report the strong genetic link between APOE p.Leu167del and the ADH phenotype in a large family.

Section snippets

Material and methods

Patients with an FH phenotype were selected from the McGill University Health Centre (MUHC). In all patients, a cascade screening of first- and second-degree relatives is offered. Clinical FH were suspected when total cholesterol is above 7 mmol/L, LDL-cholesterol is above 5 mmol/L and triglycerides are below 3 mmol/L. The protocol for blood sampling, family studies and DNA analysis has been approved by the Research Ethics Board of the research institute of the MUHC. Follow-up data for a period

Results

Our proband is a 43 year-old man of Italian origin. He presented initially with an acute coronary syndrome; a coronary angiogram revealed severe three-vessel coronary artery disease. He underwent coronary artery bypass surgery. Because of the presence of tendinous xanthomas, xanthelasmas, Achilles tendons xanthomas, elevated total cholesterol and LDL-C levels (Fig. 1A,B and C), he was selected for further evaluation. The initial lipid and lipoprotein lipid profile revealed total cholesterol of

Discussion

Recently APOE p.Leu167del was reported in a kindred from France with ADH [12]. The APOE mutation was shown to segregate in a large family with elevated LDL-C. Based on kinetic studies, it was postulated that this mutation may cause a decrease in LDL clearance [12]. Furthermore, apoE is not only a ligand for the LDLR but also for many other LRPs in the LDLR family that may assist in LDL clearance and may be more affected by the mutation seen in our patient [9]. Interestingly recent data have

Acknowledgments

We wish to thank members of the kindred that participated generously in this study. The collaboration of Colette Rondeau is gratefully acknowledged. Zuhier Awan is a King AbdulAziz University Funded Scholar. The authors declare that there were no conflicts of interest.

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