Abstract
Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway.
Highlights
Coronary artery disease (CAD), the most common cause of death, is characterized by the stenosis or occlusions of coronary arteries that are mostly caused by the progressive deposition of lipids and fibrous matrix in the arterial wall [1]
A Novel Mutation in LDL receptor-related protein-6 (LRP6) Was Identified in a Family with Normolipidemic CAD
We identified a genetic variant (Y418H) of LRP6 in Chinese normolipidemic CAD family and provided several lines of evidence to show that this genetic variant was a possible defect for familial normolipidemic CAD
Summary
Coronary artery disease (CAD), the most common cause of death, is characterized by the stenosis or occlusions of coronary arteries that are mostly caused by the progressive deposition of lipids and fibrous matrix (atherosclerotic plaques) in the arterial wall [1]. The key steps of atherosclerogenesis include dysfunction of the endothelium, lipoprotein deposition, recruitment of monocytes and lymphocytes, and proliferation of smooth muscle cells [2]. Endothelial cell survival, proliferation, and migration are critical to maintain the homeostasis and normal functions of endothelium [3]. Mutations in genes MEF2A and LRP6 were previously identified as pathogenic or CAD-causing variants for familial CAD [11,12]. The detections of these loci or genes apparently increase our knowledge of understanding the molecular mechanism of CAD and may be helpful in improving the clinical treatment and drug discovery
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