ITGAV variants are associated with immune dysregulation, brain abnormalities, and very early onset Inflammatory Bowel Disease

Integrin alpha–V (ITGAV) forms heterodimers with beta subunits to regulate several cellular processes including transforming growth factor β (TGF-β) signaling. We examined three unrelated families with common disease features including two children born with congenital brain anomalies and later development of immune dysregulation, atopy, and colitis, and three fetuses with brain and developmental defects. Using whole exome and RNA sequencing and functional studies, we demonstrate that biallelic ITGAV variants caused abnormal splicing or mislocalized protein that led to dysregulated TGF-β signaling in these families. Furthermore, knockout itgav (-/-) zebrafish embryos developed brain defects with loss of microglia and juvenile itgav (-/-) zebrafish developed colitis. Together, we show the critical role of ITGAV in immune regulation and gut and brain homeostasis and disease pathogenesis. To investigate the role of itgav in the development of very early onset inflammatory bowel disease,we generated zebrafish itgav knock out line using CRISPR/Cas9 technology. We then perform gene expression profile analysis using data abtained from RNAseq from wild type zebrafish line, and itgav(-/-) line, at two timepoints (8 dpf and 50 dpf). Comparative gene expression profiling analysis between wt and itgavKO zebrafish mutant were performed to examine the transcriptomic alterations caused by itgav deficiency.