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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Amino Acid Substitution
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Animals
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Chromosomes, Human, Pair 12 / genetics
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Coronary Disease / genetics*
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Coronary Disease / metabolism
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Family Health
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Female
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Genetic Linkage
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Genetic Predisposition to Disease*
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Humans
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LDL-Receptor Related Proteins / genetics*
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LDL-Receptor Related Proteins / physiology
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Lipids / blood
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Low Density Lipoprotein Receptor-Related Protein-6
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Male
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Metabolic Syndrome / genetics*
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Metabolic Syndrome / metabolism
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Mice
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Middle Aged
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Mutation, Missense*
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NIH 3T3 Cells
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Osteoporosis / genetics
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Pedigree
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Risk Factors
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Signal Transduction
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Wnt Proteins / metabolism
Substances
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LDL-Receptor Related Proteins
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LRP6 protein, human
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Lipids
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Low Density Lipoprotein Receptor-Related Protein-6
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Lrp6 protein, mouse
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Wnt Proteins