Genetic and Molecular Drivers of the Schizophrenia-Associated 3q29 Deletion

Emory University, Atlanta GA

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Abstract

3q29 deletion syndrome is caused by a recurrent, typically de novo 1.6 Mb heterozygous deletion that is associated with a range of neuropsychiatric phenotypes, including mild to moderate intellectual disability, autism, anxiety, and a 40-fold increased risk for schizophrenia. The high risk conferred by this deletion for neuropsychiatric phenotypes, coupled with its relatively low complexity (22 genes in the deletion interval), make it ideal for molecular dissection. Our team at Emory University has created the first mouse model of 3q29 deletion syndrome, and we show behavioral deficits consistent with compromised neurodevelopment. This model is therefore an excellent tool for interrogating the precise genetic and molecular mechanisms underlying 3q29 deletion syndrome. We propose using this model to a) identify the range of behaviors and other phenotypic manifestations with the largest departure from wild type; b) systematically pare the interval down to the minimal genes responsible for behavioral phenotypes by creating sub-deletion mice and assessing behavior; and c) identify the genes and pathways that are the molecular drivers of 3q29 deletion syndrome by evaluating transcriptional and proteomic changes in 3 distinct brain regions in full deletion and sub-deletion mice. Data from this project will be compared to our companion NIH-funded project where we are investigating molecular signatures in cells from human patients (?Modeling the Human Neuronal Phenotype of the Schizophrenia-Associated 3q29 Deletion,? 1 R01 MH110701). Understanding the specific biological processes disrupted in 3q29 deletion syndrome may provide a molecular window into key neurodevelopmental processes relevant to neuropsychiatric phenotypes, and can serve as a scaffold for integrating other targets identified in genetic studies of schizophrenia, autism, and intellectual disability. All molecular data and mouse lines will be readily and rapidly shared through NIH-approved databases and repositories.