APOE p.Leu167del mutation in familial hypercholesterolemia
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.
References (29)
- et al.
Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study
Lancet
(2013 Apr 13) - et al.
Prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia
Atherosclerosis
(2009 Nov) - et al.
Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci
Am J Hum Genet
(2012 Nov 2) - et al.
Genetic determinants of plasma triglycerides
J Lipid Res
(2011) - et al.
Society guidelines 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. 2012 recommendations
Can J Cardiol
(2013) - et al.
Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia
Atherosclerosis
(2012 Jun) - et al.
Multiplex ligation-dependent probe amplification of LDLR enhances molecular diagnosis of familial hypercholesterolemia
J Lipid Res
(2005 Feb) - et al.
Monogenic hypercholesterolemia: new insights in pathogenesis and treatment
J Clin Invest
(2003 Jun) - et al.
In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia
J Clin Invest
(1986 Nov) - et al.
Mutations in PCSK9 cause autosomal dominant hypercholesterolemia
Nat Genet
(2003 Jun)
Proprotein Convertase Subtilisin Kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies
Curr Pharm Des
Molecular spectrum of autosomal dominant hypercholesterolemia in France
Hum Mutat
Reelin, lipoprotein receptors and synaptic plasticity
Nat Rev Neurosci
Lipoprotein glomerulopathy
Curr Opin Lipidol
Cited by (83)
Advances in familial hypercholesterolemia
2024, Advances in Clinical ChemistryA Machine Learning Model to Aid Detection of Familial Hypercholesterolemia
2023, JACC: AdvancesRare monogenic disorders of cholesterol metabolism
2022, Cholesterol: From Chemistry and Biophysics to the ClinicAPOE gene variants in primary dyslipidemia
2021, AtherosclerosisImprovement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis
2021, JACC: AsiaCitation Excerpt :Thus, to make our results more rigorous, participants with LDLR plus STAP1 variants were not categorized as double heterozygotes in the present study. The APOE gene accounts for a significant fraction of the variation in plasma cholesterol levels and serves a vital role in the lipid metabolism (25). Marduel et al. (26) reported an exceptionally large family including 14 members with ADH and confirmed a variant p.Leu167del in the APOE gene, previously reported to be associated with familial combined hyperlipidemia, also involved in ADH.
Interrogation of selected genes influencing serum LDL-Cholesterol levels in patients with well characterized NAFLD
2021, Journal of Clinical Lipidology