Spatiotemporal 7q11.23 Protein Network Implicates the GTF2I-PRKDC-DDR Pathway During Early-Fetal Brain Development in Psychiatric Diseases

Abstract

Background: Recurrent deletions and duplications of chromosome 7q11.23 copy number variants (CNVs) are associated with several psychiatric disorders. Previous works showed GTF2I associated with Williams-Beuren syndrome, but pathways affected by GTF2I are poorly defined. Although phenotypic abnormalities have been observed in patients and animal models, the targeted human brain regions, developmental stages, protein networks, and signaling pathways, influenced by this CNV remain unclear. Results: Topological changes were observed in protein-protein interaction (PPI) networks throughout different stages of brain development. Early and late fetal periods of development in the cortex, striatum, hippocampus, and amygdale were observed as the vital periods and regions for 7q11.23 CNV proteins. As a driver gene, GTF2I interacted with PRKDC and BRCA1 to involve in DNA Damaging Response (DDR) pathway. The physical interaction between GTF2I with PRKDC was confirmed experimentally by the liquid chromatography-tandem mass spectrometry (LC-MS/MS). Conclusion: We identified that striatum, hippocampus, and amygdala are crucial regions for establishing connectivity between 7q11.23 proteins and their partners in early and late fetal periods. Our results suggested that GTF2I-PRKDC-DDR and GTF2I-BRCA1-DDR pathway is crucial for the 7q11.23 CNV genes to contribute to the pathogenesis of psychiatric diseases.