title: Rare nonconservative LRP6 mutations are associated with metabolic syndrome.
abstract: A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.
authors.affiliation: Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Singh
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.forename: Mohsen
authors.initials: M
authors.lastname: Fathzadeh
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Liu
authors.forename: Gwang-Woong
authors.initials: GW
authors.lastname: Go
authors.forename: Lakshman
authors.initials: L
authors.lastname: Subrahmanyan
authors.forename: Saeed
authors.initials: S
authors.lastname: Faramarzi
authors.forename: William
authors.initials: W
authors.lastname: McKenna
authors.forename: Arya
authors.initials: A
authors.lastname: Mani
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003327:Coronary Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D005060:Europe; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006031:Glycosylation; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010802:Phylogeny; D016415:Sequence Alignment; D014481:United States; D051153:Wnt Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins
keywords: LRP6; coronary artery disease; metabolic syndrome; mutation