Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux |
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Authors: | Lu Weining van Eerde Albertien M Fan Xueping Quintero-Rivera Fabiola Kulkarni Shashikant Ferguson Heather Kim Hyung-Goo Fan Yanli Xi Qiongchao Li Qing-Gang Sanlaville Damien Andrews William Sundaresan Vasi Bi Weimin Yan Jiong Giltay Jacques C Wijmenga Cisca de Jong Tom P V M Feather Sally A Woolf Adrian S Rao Yi Lupski James R Eccles Michael R Quade Bradley J Gusella James F Morton Cynthia C Maas Richard L |
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Institution: | Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. |
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Abstract: | Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR. |
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