Neuroscience perspective| Volume 60, ISSUE 6, P534-537, September 15, 2006

Making the Case for a Candidate Vulnerability Gene in Schizophrenia: Convergent Evidence for Regulator of G-Protein Signaling 4 (RGS4)

  • Pat Levitt
    Address correspondence to Dr. Pat Levitt, Vanderbilt Kennedy Center for Research on Human Development, PO Box 40 Peabody, Vanderbilt University, Nashville, TN 37203
    Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee

    Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
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  • Philip Ebert
    Department of Pharmacology, Vanderbilt University, Nashville, Tennessee
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  • Karoly Mirnics
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Vishwajit L. Nimgaonkar
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • David A. Lewis
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania

    Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania
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      Both genetic and environmental factors have been associated with an increased risk for schizophrenia. These factors are not mutually exclusive; a single gene can be a genetic factor (due to a mutation in the gene sequence) and a target of a physiological response to an environmental stimulus, both with the common endpoint of altered expression of the gene. Regulator of G-protein signaling 4 (RGS4) has been implicated as such a gene from three lines of evidence. First, a subset of genetic studies revealed an association between schizophrenia and non-functional polymorphisms in the RGS4 gene. Second, across the cortical mantle the expression of RGS4 mRNA is decreased in a diagnosis-specific manner in subjects with schizophrenia. Third, neurobiological studies demonstrate that RGS4 is highly responsive to environmental stimuli and capable of modulating the function of G-protein coupled neurotransmitter receptors implicated in schizophrenia. RGS4 is an example of a molecule that may underlie increased vulnerability through either genetic or non-genetic mechanisms, which we suggest may be typical of other genes in a complex, polygenic disorder such as schizophrenia.

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