Microdeletions of the 22q11 locus are the only known genetic lesions that increase an individual's risk for schizophrenia to a striking 25-31 times over the general population risk, a level comparable to the risk of an individual born to two schizophrenic parents. These microdeletions are present among adult schizophrenics and cases of severe childhood onset schizophrenia at rates significantly higher than in the general population. Based on our results from an extensive, detailed association analysis of all individual genes from the 22q11 locus, we propose here to use gene targeting and chromosomal engineering approaches to generate 3 mouse models that will help us understand the biological basis of the increased schizophrenia risk associated with this region. Specifically, we propose to disrupt a 250 Kb subregion that we believe carries most, if not all the genetic elements responsible for the striking increase for schizophrenia risk associated with this locus. We also propose to generate general or conditional deletions of two individual genes from this locus which, according to our genetic studies in patients, may account for a large part of the disease risk attributed to this region. We propose to examine the strains of mice that we will generate for behavioral phenotypes that may serve as models of schizophrenia-related endophenotypes (components of pathophysiological processes mediating between predisposing genes and clinical diagnosis). Furthermore, and because gray matter loss is the most consistent feature in brains of schizophrenic patients, we will address the possibility of generic or spatially restricted neuron or neuropil loss in the brains of the mutant mice using a battery of sophisticated histochemical and imaging approaches. Finally, we will use oligonucleotide microarrays to address the nature of the molecular and physiological targets affected in the brain by the disruption of individual genes or clusters of genes. Analysis of expression patterns in the brains of mice that carry well-defined genetic deficits associated with schizophrenia in humans will provide a more accurate and reproducible profiling of gene expression associated with the disease. This comprehensive approach, in conjunction with our ongoing genetic and neurocognitive studies in patients, will provide important insights into the biological processes underlying the increased schizophrenia risk associated with this region. Furthermore, the engineered mouse strains will also facilitate the identification of novel and more specific compounds with neuroleptic properties. The design of such compounds can be directed by the knowledge of individual genes from the deleted region that contribute to schizophrenia susceptibility. This will be an unprecedented situation in schizophrenia genetics and pharmacotherapy.
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