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 journalArticle

134 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)616-632
Number of pages17
JournalAmerican journal of human genetics
Volume80
Issue number4
DOIs
StatePublished - Apr 2007

Fingerprint

Vesico-Ureteral Reflux
Urinary Tract
Multiple Abnormalities
Gene Dosage
Ureter
Chronic Kidney Failure
Young Adult
Urinary Bladder
Urine
Ligands
Phenotype
Cakut
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Lu, W., Van Eerde, A. M., Fan, X., Quintero-Rivera, F., Kulkarni, S., Ferguson, H., ... Maas, R. L. (2007). Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. American journal of human genetics, 80(4), 616-632. https://doi.org/10.1086/512735

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

In: American journal of human genetics, Vol. 80, No. 4, 04.2007, p. 616-632.

Research output: Contribution to journalArticle

Lu, W, Van Eerde, AM, Fan, X, Quintero-Rivera, F, Kulkarni, S, Ferguson, H, Kim, HG, Fan, Y, Xi, Q, Li, QG, Sanlaville, D, Andrews, W, Sundaresan, V, Bi, W, Yan, J, Giltay, JC, Wijmenga, C, De Jong, TPVM, Feather, SA, Woolf, AS, Rao, Y, Lupski, JR, Eccles, MR, Quade, BJ, Gusella, JF, Morton, CC & Maas, RL 2007, 'Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux', American journal of human genetics, vol. 80, no. 4, pp. 616-632. https://doi.org/10.1086/512735
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. / Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. In: American journal of human genetics. 2007 ; Vol. 80, No. 4. pp. 616-632.
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AU - Lu, Weining

AU - Van Eerde, Albertien M.

AU - Fan, Xueping

AU - Quintero-Rivera, Fabiola

AU - Kulkarni, Shashikant

AU - Ferguson, Heather

AU - Kim, Hyung Goo

AU - Fan, Yanli

AU - Xi, Qiongchao

AU - Li, Qing Gang

AU - Sanlaville, Damien

AU - Andrews, William

AU - Sundaresan, Vasi

AU - Bi, Weimin

AU - Yan, Jiong

AU - Giltay, Jacques C.

AU - Wijmenga, Cisca

AU - De Jong, Tom P.V.M.

AU - Feather, Sally A.

AU - Woolf, Adrian S.

AU - Rao, Yi

AU - Lupski, James R.

AU - Eccles, Michael R.

AU - Quade, Bradley J.

AU - Gusella, James F.

AU - Morton, Cynthia C.

AU - Maas, Richard L.

PY - 2007/4

Y1 - 2007/4

N2 - 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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