It is becoming increasingly clear that neurodevelopmental disorders with very distinct clinical presentations nonetheless share common genetic mechanisms, and an increasing number of genes are now linked to multiple forms of neurological disease. These genes, which “confer risk across diagnostic boundaries,” are frequently found to be higher-level developmental regulators that orchestrate neuron differentiation, migration, and synaptic connectivity.
The AUTS2 gene is one of those higher regulators, serving as a component of a chromatin-modifying complex that is called upon to regulate the expression of downstream cascades of neurodevelopmental genes. This activity is called upon in a dynamic pattern, within specific cell populations in a specific sequence across the developing brain, as the neurons begin to form, mature, and develop synaptic connections that must be maintained into adulthood.
Like many of these higher-level regulators, AUTS2 is a very large, complex gene that encodes distinct proteins from unique alternative promoters; the malfunction of one or both protein isoforms can lead to a wide range of neurological disorders—including autism spectrum disorder, intellectual disability, attention deficit hyperactivity disorder, feeding disorders, epilepsy, and susceptibility to addiction. The goal of PNRI’s Stubbs Lab is to understand the unique functions of AUTS2 protein isoforms, their dynamic regulation, and mechanisms through which they interact to generate risk to different types of disease.