title: Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux.
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.
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weining
authors.initials: W
authors.lastname: Lu
authors.forename: Albertien M
authors.initials: AM
authors.lastname: van Eerde
authors.forename: Xueping
authors.initials: X
authors.lastname: Fan
authors.forename: Fabiola
authors.initials: F
authors.lastname: Quintero-Rivera
authors.forename: Shashikant
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Heather
authors.initials: H
authors.lastname: Ferguson
authors.forename: Hyung-Goo
authors.initials: HG
authors.lastname: Kim
authors.forename: Yanli
authors.initials: Y
authors.lastname: Fan
authors.forename: Qiongchao
authors.initials: Q
authors.lastname: Xi
authors.forename: Qing-Gang
authors.initials: QG
authors.lastname: Li
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.forename: William
authors.initials: W
authors.lastname: Andrews
authors.forename: Vasi
authors.initials: V
authors.lastname: Sundaresan
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.forename: Jacques C
authors.initials: JC
authors.lastname: Giltay
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: Tom P V M
authors.initials: TP
authors.lastname: de Jong
authors.forename: Sally A
authors.initials: SA
authors.lastname: Feather
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Yi
authors.initials: Y
authors.lastname: Rao
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Michael R
authors.initials: MR
authors.lastname: Eccles
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Quade
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
authors.forename: Richard L
authors.initials: RL
authors.lastname: Maas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002460:Cell Line; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D041322:Chromosomes, Human, Y / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010375:Pedigree; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D014551:Urinary Tract / Q000002:abnormalities*; D014718:Vesico-Ureteral Reflux / Q000235:genetics* / Q000473:pathology; D000097905:Roundabout Proteins
chemical_list: D017931:DNA Primers; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; C498890:ROBO2 protein, human; D000097905:Roundabout Proteins; C492289:SLIT1 protein, human