A Mouse Mutation That Dysregulates Neighboring and Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome.

was originally discovered as the gene disrupted by a translocation in human twins with Autism spectrum disorder, intellectual disability, and epilepsy. Since that initial finding, -linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that is required for fundamental steps of neurodevelopment. However, genotype-phenotype correlations in this region are complicated, because most mutations could also involve neighboring genes. Of particular interest is the nearest downstream neighbor of , , which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse () mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between and and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human -linked phenotypes very well. In addition to abnormalities in growth, craniofacial structure, learning and memory, and behavior, 16Gso homozygotes display distinct pathologies of the cerebellum and hippocampus that are similar to those associated with autism and other types of -linked neurological disease. Analyzing mutant cerebellar and hippocampal transcriptomes to explain this pathology, we identified disturbances in pathways related to neuron and synapse maturation, neurotransmitter signaling, and cellular stress, suggesting possible cellular mechanisms. These pathways, coupled with the translocation's selective effects on isoforms and coordinated dysregulation of , suggest novel hypotheses regarding the etiology of the human "AUTS2 syndrome" and the wide array of neurodevelopmental disorders linked to variance in this genomic region.