Recent exciting progress in schizophrenia genetics has revealed genomic copy number changes with large susceptibility for disease. Large (~1Mb), heterozygous, typically de novo copy number changes on chromosomes 1q21, 15q11, 15q13, 16p11, 22q11, and most recently a deletion on chromosome 3q29 are all enriched in SZ patients relative to controls. Interestingly, these copy number changes are also enriched in autism and intellectual disability cohorts. However, these discoveries have been unaccompanied by identification of the specific gene responsible for the phenotype(s). At Emory we have established an interdisciplinary team that consists of the labs of Stephen Warren, Tamara Caspary and David Weinshenker, and our initial goal is to recapitulate the human 3q29 interval by creating mouse models of the deletion and reciprocal duplication, and ascertaining the behavioral consequences on multiple mouse strain backgrounds using a comprehensive battery of tests. Ascertaining the full behavioral spectrum in alternate genomic contexts will allow us to elicit differences that are predicated on mouse strain background, recapitulating the variable phenotypes observed in humans. For the microdeletion, we further propose to create a series of smaller overlapping deletions in the two strains with the most robust phenotypes. In this way we will establish the minimal deletion (and therefore minimal genes) required for a behavioral phenotype. This approach will enable us to 1) create models of the 3q29 deletion and duplication syndromes, 2) discern whether disruption of an individual gene or combination of genes are responsible for the SZ, ID and autism-like features exhibited by deletion patients or if distinct genes are responsible for the different phenotypes and 3) identify the causative gene(s) which will, in turn, provide a molecular handle through which these neuropsychiatric conditions can be better understood and treated. Using these mouse models combined with behavioral testing, we expect to identify the gene responsible for the 3q29 deletion phenotype, a major candidate gene for schizophrenia, intellectual disability, and autism. Thus this grant will develop a valuable mouse model and provide a molecular handle of the genetic pathways that the community requires to advance psychiatric genetic research.
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|Glassford, Megan R; Rosenfeld, Jill A; Freedman, Alexa A et al. (2016) Novel features of 3q29 deletion syndrome: Results from the 3q29 registry. Am J Med Genet A 170A:999-1006|
|Mulle, J G (2015) The 3q29 deletion confers >40-fold increase in risk for schizophrenia. Mol Psychiatry 20:1028-9|