LRP6 mutation in a family with early coronary disease and metabolic risk factors |
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| 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 |
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| Institution: | Department of Internal Medicine, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510, USA. arya.mani@yale.edu |
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| 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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