학술논문
Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux.
Document Type
Academic Journal
Author
Lu W; Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.; 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 TP; Feather SA; Woolf AS; Rao Y; Lupski JR; Eccles MR; Quade BJ; Gusella JF; Morton CC; Maas RL
Source
Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0002-9297 (Print) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
Subject
Language
English
ISSN
0002-9297
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.