Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux.
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.
Lu
Weining
W
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
van Eerde
Albertien M
AM
Fan
Xueping
X
Quintero-Rivera
Fabiola
F
Kulkarni
Shashikant
S
Ferguson
Heather
H
Kim
Hyung-Goo
HG
Fan
Yanli
Y
Xi
Qiongchao
Q
Li
Qing-Gang
QG
Sanlaville
Damien
D
Andrews
William
W
Sundaresan
Vasi
V
Bi
Weimin
W
Yan
Jiong
J
Giltay
Jacques C
JC
Wijmenga
Cisca
C
de Jong
Tom P V M
TP
Feather
Sally A
SA
Woolf
Adrian S
AS
Rao
Yi
Y
Lupski
James R
JR
Eccles
Michael R
MR
Quade
Bradley J
BJ
Gusella
James F
JF
Morton
Cynthia C
CC
Maas
Richard L
RL
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
D017931:DNA Primers; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; C498890:ROBO2 protein, human; D000097905:Roundabout Proteins; C492289:SLIT1 protein, human