Many types of neuropsychiatric conditions have a significant genetic component, although they are generally thought to involve a mix of interacting genes. However, some disorders can also be driven by rare mutations in single genetic loci, highlighting genes with basic and pivotal roles in neurodevelopment. One such locus, AUTS2, was originally discovered as disrupted in a pair of autistic twins. However, AUTS2 mutations have since been linked to a wide range of neurological disorders, including epilepsy, schizophrenia, bipolar disorder, addictive behaviors to name a few. This single genetic region is thus implicated in an exceptionally broad range of neuropsychiatric disorders with profound societal impact. However, the way that AUTS2-region mutations predispose to these diseases is not well understood. Complicating the genetic picture, most human AUTS2 mutations are genomic rearrangements that could impact the functions of other neighboring genes. Of particular interest in this regard is WBSCR17, which is linked to AUTS2 in a conserved topographically associating domain (TAD), suggesting co-regulation of the genes. While Auts2 mouse ?knockout? mutations express certain phenotypes that could be considered parallel to certain neuropsychiatric traits, they have not provided a compelling model for AUTS2-linked disease. This project is focused on a novel mouse mutation, called 16Gso, which disrupts the Wbscr17-Auts2 TAD and dysregulates both genes. Despite this complex genetic effect, 16Gso mutants display morphological, behavioral, and brain structural abnormalities that model human AUTS2 phenotypes strikingly well. We hypothesize that Wbscr17 contributes to 16Gso and AUTS2-linke human neurological phenotypes by interacting with Auts2 in a basic cellular pathway required for the extension, survival, and connectivity of neuronal processes in the developing and adult brain. Further we propose that disturbance of this pathway leaves affected individuals susceptible to a wide range neuropsychiatric disease. This proposal is focused on addressing these hypotheses by defining the contributions of Wbscr17 to 16Gso phenotypes, and the genetic interactions between Wbscr17 and Auts2. We will investigate the cellular functions regulated by the two loci in a cellular model, and define the regulatory mechanisms that control these linked genes. Together these data will provide novel explanations for genotype:phenotype correlations in a genetic region linked broadly to susceptibilities to human neurological disease.
Mutations in the human AUTS2 genetic locus have been implicated in an exceptionally broad array of neuropsychiatric disorders with profound societal impact, suggesting a profound and basic role in neurodevelopment. However, the region is complex, and many AUTS2-region mutations are genetic rearrangements that could affect neighboring genes. This proposal aims to develop a genetic model for AUTS2- linked disease, investigating genetic interactions and regulatory mechanisms controlling a basic cellular pathway that is key to neuropsychiatric health.
