A Mouse Mutation That Dysregulates NeighboringGalnt17andAuts2Genes Is Associated with Phenotypes Related to the Human AUTS2 Syndrome

Abstract

AUTS2 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, AUTS2-linked mutations and variants have been associated with a very broad array of neuropsychiatric disorders, sugg esting that AUTS2 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 AUTS2, GALNT17, which encodes a brain-expressed N-acetylgalactosaminyltransferase of unknown brain function. Here we describe a mouse (Mus musculus) mutation, T(5G2;8A1)GSO (abbreviated 16Gso), a reciprocal translocation that breaks between Auts2 and Galnt17 and dysregulates both genes. Despite this complex regulatory effect, 16Gso homozygotes model certain human AUTS2-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 AUTS2-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 Auts2 isoforms and coordinated dysregulation of Galnt17, 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.

Divergent projections of the prelimbic cortex mediate autism- and anxiety-like behaviors

“…Sequencing results of brain tissue samples from three ASD mutant mice revealed 5 overlapping differential genes ( Alpk1 , Dock9 , Shank2 , Syne1, and Tmem74 ) (Fig. 1a, b ) [ 30 – 32 ]. Among the downregulated genes, Dock9 was reported to be associated with peripheral cancers [ 33 ].…”

Positive selection of neuregulin 1 (NRG-1) among three long-lived vertebrates

“…Using PAML, we were able to detect evidence of positive selection in three of the examined orthologs, two of which (NRG-1 and GALNT17) showed evidence of positive selection exclusively with the long-lived species B. musculus and C. abingdonii . Notably, NRG-1 and GALNT17 are both associated with neural development and function (Mei and Xiong 2008; Weisner, et al 2019). NRG-1 acts in vivo as a direct ligand for ERBB3 and ERBB4, members of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases.…”

“…GALNT17 is less well characterized, but it is expressed in multiple cell types in the brain and serves as an N-acetylgalactosaminyltransferase that ultimately affects cell adhesion and motility, pinocytosis, and lamellipodia formation (Nakayama, et al 2012). Deletion of GALNT17 occurs in Williams-Beuren syndrome, and likely contributes to the associated phenotype (Merla, et al 2002; Weisner, et al 2019).…”

AUTS2 Gene: Keys to Understanding the Pathogenesis of Neurodevelopmental Disorders

“…This is likely correlated with the observation that the severity of the symptoms of AUTS2 syndrome is prominent in individuals with disruption at the 3′ end of the AUTS2 locus [ 14 ]. Mice lacking Auts2 exhibit hypoplasia in the dentate gyrus as well as in the cerebellum [ 34 , 39 , 45 ]. These findings suggest that AUTS2 plays a key role in neural development in the brain.…”