Candidate Genes for Vesico-Ureteral Reflux

Abstract

PURPOSE Vesico-ureteral reflux (VUR) is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter. VUR is a major contributing factor to end-stage renal disease in paediatric patients. We aim to identify genetic factors contributing to VUR. MATERIAL AND METHODS In a collaborative study we investigated a man with a de novo translocation, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for the SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, two novel ROBO2 intracellular missense variants were identified that segregate with CAKUT and VUR in two unrelated families. SLIT-ROBO signalling is involved in the development of the ureteric bud. To investigate the involvement of 12 other functional candidate genes (mostly involved in ureteric budding) and two reported loci in VUR, we performed a linkage study in four large, Dutch, multi-generational families with multiple affected individuals. RESULTS We were unable to detect linkage to any of the genes and loci and could exclude the GDNF, RET, SLIT2, SPRY1, PAX2, AGTR2, UPK1A and UPK3A genes and the 1p13 and 20p13 loci from linkage to VUR. CONCLUSIONS Mutations in ROBO2 contribute to the development of VUR in a small subset of patients. Our results provide further evidence that there appears to be genetic heterogeneity in VUR.