Disruption of ROBO2 Is Associated with Urinary Tract Anomalies and Confers Risk of Vesicoureteral Reflux

摘要: Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by retrograde flow urine from bladder into ureter associated with nephropathy, cause 15% end-stage renal disease in children young adults. We investigated man de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral ureterovesical junction defects. This translocation disrupts ROBO2, which encodes transmembrane receptor for SLIT ligand, produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling vitro. In addition, we identified two novel intracellular missense variants segregate CAKUT unrelated families. Adult heterozygous mosaic mutant mice reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate pathway pathogenesis subset human VUR.