Special Guest Lecture - Katherine Roche, PhD, Senior Investigator, National Institute of Neurological Disorders and Stroke, National Institutes of Health

Synaptic dysfunction underlying neurodevelopmental disorders: Insights from rare variants Abstract: As whole exome and genome sequencing become more prevalent, hundreds of genes associated with neurodevelopmental disorders (NDDs) have been identified. Among these are numerous genes encoding synaptic proteins that can have highly penetrant rare variants that are pathogenic. Our lab focuses on two families of postsynaptic proteins, NMDA receptors and neuroligins, that are high confidence NDD genes. We explore the synaptic consequences of these pathogenic de novo mutations. GRIN genes encode NMDA receptors subunits, which are glutamate receptors that are essential for neuronal development, learning, and memory. Endogenous NMDA receptors are typically composed of two GluN1 subunits and two GluN2 subunits. Our recent findings identify a cluster of pathogenic variants that lead to disruption of the PDZ binding site in GluN2B and protein destabilization. In other studies, our group is making mouse models to study pathogenic truncating mutations in GRIN2B and GRIN2A to determine the message stability, protein expression, and synaptic localization. By revealing the mechanistic consequences of genetic variants of NMDAR subunits, we hope to shed light on the mechanisms of disease and develop better therapeutics. Similarly, we are studying the effects of pathogenic rare variants on neuroligin function. We have identified multiple clusters of highly penetrant variants in NLGN4X that lead to protein trafficking deficits. In collaborations with National Center for Advancing Translational Sciences (NCATS), we have conducted drug screens and have several candidate molecules for rescuing the trafficking deficits in NLGN4X variants. We hope our discoveries can facilitate development of therapeutics for NDD disorders.