title: Functional analysis LRP6 novel mutations in patients with coronary artery disease.
abstract: BACKGROUND
  Genetic architecture of coronary artery disease (CAD) is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6) gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients.
  
  
  METHODS
  We systemically sequenced all the exons and promoter region of LRP6 gene in a sample of 380 early onset CAD patients and 380 control subjects in Chinese.
  
  
  RESULTS
  In total, we identified 5 patient-specific mutations including K82N (two patients), S488Y (one patient), P1066T (two patients), P1206H (two patients) and I1264V (one patient) All these mutations located at the extracellular domain of LRP6 gene. In vitro functional analysis of patient-specific mutations demonstrated that these mutations resulted in a significant reduction in both protein level transporting to cell membrane and downstream Wnt signal activity. Furthermore, we found that LRP6 novel mutations attenuated proliferation and migration of human umbilical vein endothelial cells (HUVECs) when compared with wild type (WT) LRP6.
  
  
  CONCLUSIONS
  Our results demonstrated that these loss-of-function variants might contribute to disease liability in a subset of CAD and defects in Wnt signal activation might be important contributing factors for the onset of CAD.
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China ; Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, China.
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, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China ; Echocardiography Laboratory, Sichuan Provincial Hospital, Chengdu, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Peng
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Haoran
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China ; Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Ding
authors.affiliation: The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China ; Genetic Diagnosis Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D016415:Sequence Alignment; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins