LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors

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),...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2007-03, Vol.315 (5816), p.1278-1282
Main Authors: Mani, Arya, Radhakrishnan, Jayaram, Wang, He, Mani, Alaleh, Mani, Mohammad-Ali, Nelson-Williams, Carol, Carew, Khary S, Mane, Shrikant, Najmabadi, Hossein, Wu, Dan, Lifton, Richard P
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Amino Acid Substitution
Animals
Biological and medical sciences
Cardiology. Vascular system
Cardiovascular disease
Cholesterols
Chromosomes, Human, Pair 12 - genetics
Coronary Disease - genetics
Coronary Disease - metabolism
Coronary heart disease
Diabetes
Diabetes mellitus
Disease models
Family Health
Female
Genetic Linkage
Genetic mutation
Genetic Predisposition to Disease
Heart
Humans
Hypertension
LDL-Receptor Related Proteins - genetics
LDL-Receptor Related Proteins - physiology
Lipids - blood
Lod score
Low Density Lipoprotein Receptor-Related Protein-6
Male
Medical sciences
Metabolic syndrome
Metabolic Syndrome - genetics
Metabolic Syndrome - metabolism
Mice
Middle Aged
Mutation
Mutation, Missense
NIH 3T3 Cells
Osteoporosis
Osteoporosis - genetics
Pedigree
Phenotypic traits
Predisposing factors
Risk Factors
Signal Transduction
Wnt Proteins - metabolism
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Summary: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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1136370