It is now evident that many cases of psychiatric and neurodevelopmental disorders, as well as disorders of cognitive function, are due to highly penetrant, rare genetic variants. 22q11.2 deletion is a prominent example of such a variant. Carriers of deletions in chromosome 22q11.2, which predominantly occur de novo, exhibit a spectrum of cognitive deficits and develop schizophrenia in adolescence or early adulthood at a rate of 25-30%. Recurrent 22q11.2 deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Because of its leading role in the genetic landscape of psychiatric disease and cognitive dysfunction, functional analysis of the 22q1.2 deletion holds great promise for providing the biological insights necessary for development of new treatments for these conditions. In this project, we propose to study the impact of 22q11.2 deletions on neuronal structure and function in exquisite depth. Our proposed research focuses on this highly significant problem using state-of-the-art techniques, reliable animal models, and patient- derived neurons, and is designed to improve our understanding of the chain of events leading from the mutation, through its effects on neural cells and circuits, to clinical phenotype and inform the development of new therapeutics. A major aspect of our effort will be to implement carefully controlled translational paradigms to test many of the alterations that we find in mouse models in neurons from patients. Along these lines, we propose to pursue detailed comparative studies between human and mouse, using cortical neurons derived from induced pluripotent stem cells (iPSCs) from humans carrying the 22q11.2 deletion. The strength of this approach is undeniable since it will allow in-depth analysis at the level of the individual neuron and synapse, which are otherwise inaccessible in patients.
Recent advances in genomics have confirmed conclusively a significant role of copy number variants (CNVs) in psychiatric disorders and cognitive dysfunction. One CNV with prominent significance involves deletions on chromosome 22q11.2, which we propose to study in exquisite depth. We offer to take advantage of the reliable mouse models that we have generated for this deletion and human neurons that we have derived from induced pluripotent stem cells (iPSCs) from patients carrying this deletion for a series of in-depth studies designed to improve our understanding of the chain of events leading from the mutation to clinical phenotype and inform the development of new therapeutics.
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