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.
3q29 deletion syndrome is caused by a deletion of 22 genes and is associated with high risk for intellectual disability, autism, anxiety, and schizophrenia, but it is not known which of the 22 genes contributes to these phenotypes. We propose to use a mouse model of the syndrome to promote or exclude target genes, until we have the minimum gene or genes that cause the phenotype; we will also use our mouse model to identify the molecular pathways that are disrupted in 3q29 deletion syndrome. This project will contribute to our understanding of the pathophysiology underlying neurodevelopmental and neuropsychiatric phenotypes, including autism and schizophrenia.
