Disruption of ROBO2 Is Associated with Urinary Tract Anomalies and Confers Risk of Vesicoureteral Reflux

• Published in: American journal of human genetics Vol. 80; no. 4; pp. 616 - 632
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.04.2007; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Amino Acid Sequence; Animals; Biological and medical sciences; Blotting, Southern; Blotting, Western; Cell Line; Chromosomes, Human, Pair 3 - genetics; Chromosomes, Human, Y - genetics; Congenital diseases; DNA Mutational Analysis; DNA Primers; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic disorders; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; In Situ Hybridization, Fluorescence; Kidney diseases; Male; Medical genetics; Medical sciences; Mice; Molecular and cellular biology; Molecular Sequence Data; Mutation, Missense - genetics; Nephrology; Nephrology. Urinary tract diseases; Nerve Tissue Proteins - metabolism; Pathology; Pedigree; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Translocation, Genetic - genetics; Urinary system involvement in other diseases. Miscellaneous; Urinary Tract - abnormalities; Urinary tract. Prostate gland; Vesico-Ureteral Reflux - genetics; Vesico-Ureteral Reflux - pathology; Human; Urinary system disease; Association; Vesicoureteral reflux; Risk factor; Genetics; Risk; Bladder disease; Anomaly; Urinary tract disease; Disruption; Urinary tract
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/512735

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.