Article

LRP6 mutation in a family with early coronary disease and metabolic risk factors.

Department of Internal Medicine, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510, USA.
Science (impact factor: 31.2). 04/2007; 315(5816):1278-82. DOI:10.1126/science.1136370 pp.1278-82
Source: PubMed

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.

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Keywords

autosomal dominant
 
co-receptor
 
conserved residue
 
encodes
 
epidermal growth factor-like domain
 
genetic linkage
 
hyperlipidemia
 
impairs Wnt signaling
 
leading cause
 
missense mutation
 
multiple cardiovascular risk factors
 
mutation
 
results link
 
short segment
 
substitutes cysteine
 
traits
 
Wnt signaling
 
Wnt signaling pathway