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LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors
Arya Mani,1*Jayaram Radhakrishnan,1He Wang,2Alaleh Mani,3Mohammad-Ali Mani,4Carol Nelson-Williams,1Khary S. Carew,1Shrikant Mane,1Hossein Najmabadi,5Dan Wu,2Richard P. Lifton1*
Coronary artery disease (CAD) is the leading cause of deathworldwide and is commonly caused by a constellation of riskfactors called the metabolic syndrome. We characterized a familywith autosomal dominant early CAD, features of the metabolicsyndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis.These traits showed genetic linkage to a short segment of chromosome12p, in which we identified a missense mutation in LRP6, whichencodes a co-receptor in the Wnt signaling pathway. The mutation,which substitutes cysteine for arginine at a highly conservedresidue of an epidermal growth factor–like domain, impairsWnt signaling in vitro. These results link a single gene defectin 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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Metabolic Syndrome--What We Know and What We Don't Know: LPR6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors. Science 315: 1278-1282, 2007.
Ar. Mani, J. Radhakrishnan, H. Wang, Al. Mani, M.A. Mani, C. Nelson-Williams, K.S. Carew, S. Mane, H. Najmabadi, D. Wu, et al. (2007)
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Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease.
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|Abstract »|Full Text »|PDF »
