Rare Nonconservative LRP6 Mutations Are Associated with Metabolic Syndrome

Authors

  • Rajvir Singh,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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    • These authors contributed equally to this work.

  • Emily Smith,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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    • These authors contributed equally to this work.

  • Mohsen Fathzadeh,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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    • These authors contributed equally to this work.

  • Wenzhong Liu,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Gwang-Woong Go,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Lakshman Subrahmanyan,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • Saeed Faramarzi,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
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  • William McKenna,

    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    2. Institute of Cardiovascular Science, University College London, London, UK
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  • Arya Mani

    Corresponding author
    1. Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
    2. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
    • Correspondence to: Arya Mani, Yale Cardiovascular Research Center, 300 George Street, New Haven, CT 06511. E-mail: Arya.mani@yale.edu

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  • Communicated by Elizabeth F. Neufeld

  • Contract Grant Sponsor: NIH (1R01HL094574, 5R01HL094784).

ABSTRACT

A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation.

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