title: LRP6 mutation in a family with early coronary disease and metabolic risk factors.
abstract: Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.
authors.affiliation: Department of Internal Medicine, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510, USA. arya.mani@yale.edu
authors.forename: Arya
authors.initials: A
authors.lastname: Mani
authors.forename: Jayaram
authors.initials: J
authors.lastname: Radhakrishnan
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Alaleh
authors.initials: A
authors.lastname: Mani
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Mani
authors.forename: Carol
authors.initials: C
authors.lastname: Nelson-Williams
authors.forename: Khary S
authors.initials: KS
authors.lastname: Carew
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000818:Animals; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D003327:Coronary Disease / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000502:physiology; D008055:Lipids / Q000097:blood; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D010024:Osteoporosis / Q000235:genetics; D010375:Pedigree; D012307:Risk Factors; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D008055:Lipids; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D051153:Wnt Proteins