Manitoba has a critical, unmet need to understand and treat developmental disorders, including autism spectrum disorder. We and others have identified different types of variants in the gene called IRF2BPL associated with both autism spectrum disorder and a highly severe neurological disorder that presents in children around the age of five years old called NEDAMSS.

Although variable, NEDAMSS patients have neurological regression including loss of speech, loss of developmental milestones, seizures, and movement abnormalities where they eventually become immobile in adolescence. Beyond being an important human disease gene, IRF2BPL is an interesting gene as it is enriched in the brain and mostly unstudied.

We and our collaborators have made models of IRF2BPL in fruit flies and zebrafish. However, there are no models in mice, which are needed for translating pre-clinical drug screening studies to patients. In this proposal, we have generated two patient-specific mouse lines associated with either autism or NEDAMSS. We will characterize both of these novel mouse models, determining if there are behavioural defects as well as pathology in the brain.

Moreover, we can use these two mouse lines to discern, mechanistically, why certain mutations lead to autism spectrum disorder and other mutations lead to a severe neurological disorder like NEDAMSS. Both models will deepen our understanding of neurodevelopment and neurodegeneration.

Neurodevelopmental disorders in Manitoba

Manitoba has some of the highest rates of neurodevelopmental disorders in Canada, having specific populations where novel gene variants have been identified. Moreover, autism spectrum disorder has seen an increased prevalence in Manitoba. Importantly, few if any of these neurodevelopmental disorders or autism spectrum disorders have approved therapies that can reverse or prevent them. Hence, there is a clear need for basic studies to both inform on pathogenic mechanisms and to develop pre-clinical models for therapeutic testing.