TY - JOUR
T1 - Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux
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.
N1 - Funding Information:
We thank Roxana Peters, Robert Eisenman, Diana Donovan, Annick Turbe-Doan, and Juan Liu, for technical support; Yiping Shen, Anne Higgins, and Fowzan Alkuraya, for assistance with array CGH; Chantal Farra, for referral of the DGAP107 subject; Frank Costantini, for providing Hoxb7-GFP transgenic mice; Wellington Cardoso and Jining Lu, for help with fluorescence stereomicroscopy; and Natalia Leach, Irfan Saadi, Kate Ackerman, Azra Ligon, David Harris, Gail Bruns, Grigoriy Kryukov, Shamil Sunyaev, Monica Banerjee, Maria Bitner-Glindzicz, Sue Malcolm, Dagan Jenkins, Ramon Bonegio, and David Salant, for helpful suggestions. This work was supported by National Institutes of Health grants PO1GM061354 (to C.C.M.) and RO1DK063316 (to R.L.M.); the Hilda Gershon Sugarman Young Investigator grant from the National Kidney Foundation, a Department of Medicine Pilot Project grant, and an Evans Medical Foundation grant (to W.L.); Dutch Kidney Foundation grant C02.2009 (to J.C.G. and A.M.v.E.); a Health Research Council grant (to M.R.E.); a Kids Kidney Appeal grant, a Kidney Research UK grant, and Wellcome Trust grant 066647 (to A.S.W. and S.A.F.); and a Medical Research Council Career Establishment grant (to W.A. and V.S.).
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.
AB - 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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U2 - 10.1086/512735
DO - 10.1086/512735
M3 - Article
C2 - 17357069
AN - SCOPUS:34147151136
SN - 0002-9297
VL - 80
SP - 616
EP - 632
JO - American journal of human genetics
JF - American journal of human genetics
IS - 4
ER -
