title: Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease.
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.
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. deidei@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. ly1306386063@pku.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiovascular, PLA General Hospital, Beijing 100853, China. rainbowren301@163.com.
authors.forename: Yi-Hong
authors.initials: YH
authors.lastname: Ren
authors.affiliation: Department of Cardiovascular, PLA General Hospital, Beijing 100853, China. sunzj301@sohu.com.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. djqiu@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. yanhan@pku.edu.cn.
authors.forename: Han
authors.initials: H
authors.lastname: Yan
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China. xuyujun3506@163.com.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China. dwwang@tjh.tjmu.edu.cn.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. zhengguyan@163.com.
authors.forename: Gu-Yan
authors.initials: GY
authors.lastname: Zheng
authors.affiliation: Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung &amp; Blood Vessel Disease, Beijing 100029, China. jiedubj@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China. tianxiaoli@pku.edu.cn.|Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, Nanchang 330031, China. tianxiaoli@pku.edu.cn.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics*; D008055:Lipids / Q000032:analysis; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: C555475:LRP6 protein, human; D008055:Lipids; D060488:Low Density Lipoprotein Receptor-Related Protein-6
keywords: LDL receptor-related protein-6 (LRP6); coronary artery disease; endothelial cell dysfunction; familial; normolipidemic