Grant: Project Grant

Autism spectrum disorders (ASD), such as Smith-Magenis syndrome (SMS), are genetic brain disorders impairing brain function, causing social cognitive defects and epilepsy. These disorders pose a heavy burden on Canadian society because of the lack of proper treatment and increasing costs associated with patient care. One main hurdle is the lack of access to understanding how genetic mutations that cause ASD disrupt the brain development of patients. SMS is caused by genetic deletion of a segment of chromosome 17p11.2 (del(17)p11.2) or mutations in the RAI1 gene within the deleted segment. SMS patients show many deficits in a region of the brain called the cortex. Cortical dysfunction in SMS patients includes epilepsy, reduced cortex volume, and increased ventricle size. However, how genetic mutations cause these cortical dysfunctions remains unknown. Importantly, models of SMS do not recapitulate cortical dysfunction in human SMS patients. To overcome this barrier, this project will use human induced pluripotent stem cell (hiPSC)-derived 2D cortical neurons and 3D cortical organoids to understand how SMS-causing mutations disrupt cortical development and function. We will evaluate the extent to which RAI1 restoration could ameliorate disease features associated with different SMS mutations (i.e. RAI1 mutation, classic deletion, and large deletion). Moreover, we will study how RAI1 protein abundance is regulated at the molecular level by ubiquitination to gain insights into SMS pathogenesis and develop therapy. Overall, our efforts will provide novel insights into the mechanism by which RAI1 regulates cortical development and its potential as a therapeutic target to reverse the devastating brain defects associated with SMS.