Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

Weining Lu, Albertien M. Van Eerde, Xueping Fan, Fabiola Quintero-Rivera, Shashikant Kulkarni, Heather Ferguson, Hyung Goo Kim, Yanli Fan, Qiongchao Xi, Qing Gang Li, Damien Sanlaville, William Andrews, Vasi Sundaresan, Weimin Bi, Jiong Yan, Jacques C. Giltay, Cisca Wijmenga, Tom P.V.M. De Jong, Sally A. Feather, Adrian S. WoolfYi Rao, James R. Lupski, Michael R. Eccles, Bradley J. Quade, James F. Gusella, Cynthia C. Morton, Richard L. Maas

Research output: Contribution to journalArticlepeer-review

168 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)616-632
Number of pages17
JournalAmerican journal of human genetics
Issue number4
StatePublished - Apr 2007
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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