Williams-Beuren syndrome is caused by a recurrent de novo deletion of a ~28 genes on chromosome 7. The cognitive profile of WBS is characterized by mental retardation and an unusual hyper-social personality with a demonstrably increased interest in social engagement. The reciprocal duplication has been associated with autism spectrum disorder, separation anxiety, and language delay. These observations provide strong evidence for the hypothesis that a gene or genes in the WBS region influences social behavior, and potentially language acquisition, in a dosage sensitive manner. However, which gene(s) mediate the complete cognitive phenotype is not clear. The preponderance of evidence from partial deletions suggests a family of 3 transcription factors (the Gtf2i family) may mediate the cognitive profile. Yet the available cases do not distinguish whether it is individual genes or whether it is an overall effec of Gtf2i family dose that mediates the impact of the locus. Furthermore, regardless of which gene(s) in the locus may be causative, the actual mechanism by which these genes alter behavior is unclear. Recently, it has been observed that individuals harboring this mutation have significantly higher levels of the neuropeptide Oxytocin (Oxt) circulating in the blood, a moleculewell known to have roles in pair-bonding, social interaction, and other behaviors across all mammals, including humans. Thus one possibility is that haploinsufficiency of Gtf2i family members leads to increased neuropeptide synthesis and thus altered social drive. However, this hypothesis has not been tested functionally and any cellular or molecular intermediaries between WBS loci mutations and Oxt release are undefined. Here, we aim to leverage innovative new genome editing approaches in mice to systematically address whether haploinsufficiency in Gtf2i family members individually, or in combination, is required to mediate the full impact of loss of the locus on social behavior in mammals. We will also test the hypothesis that loss of these genes individually, or multi-gene deletions of the WBS locus, are able to increase Oxt levels, and we will use genetic approaches to test the necessity of Oxt signaling for WBS-region mediated alterations in social behavior. Finally, we will take both discovery-driven and hypothesis-driven approaches to defining the molecular and cellular consequences of these mutations in the brain.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
