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Science 315 (5816): 1278-1282

Copyright © 2007 by the American Association for the Advancement of Science

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

Arya Mani,1* Jayaram Radhakrishnan,1 He Wang,2 Alaleh Mani,3 Mohammad-Ali Mani,4 Carol Nelson-Williams,1 Khary S. Carew,1 Shrikant Mane,1 Hossein Najmabadi,5 Dan Wu,2 Richard P. Lifton1*

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.

1 Departments of Internal Medicine, Genetics and Molecular Biophysics, and Biochemistry, Howard Hughes Medical Institute and Yale University School of Medicine, New Haven, CT 06510, USA.
2 Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510, USA.
3 Department of Material Science, Amir Kabir University of Technology, Tehran 15875/4413, Iran.
4 Department of Human Sciences, Azad University of Tehran, Tehran 13185/786, Iran.
5 Genetics Research Center, The Social Welfare and Rehabilitation Sciences University, Tehran 19875/383, Iran.

* To whom correspondence should be addressed. E-mail: arya.mani{at}yale.edu (A.M.); richard.lifton{at}yale.edu (R.P.L.)

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