ROBO2 Gene Variants Are Associated with Familial Vesicoureteral Reflux

Abstract

The SLIT2 receptor ROBO2 plays a key role in the formation of the ureteric bud, and its inactivation in mice leads to supernumerary ureteric bud development, lack of ureter remodeling, and improper insertion of the ureters into the bladder. Recently, two heterozygous ROBO2 missense mutations were identified in two families with primary vesicoureteral reflux occurring in combination with congenital anomalies of the kidney and urinary tract (VUR/CAKUT). This study investigated a possible causal role of ROBO2 gene variants in 95 unrelated patients with primary VUR (n ϭ 78) or VUR/CAKUT. Eighty-two percent of all patients had a family history of genitourinary anomalies. Twenty-four ROBO2 gene variants were identified by direct sequencing of all 26 exons and the exon-intron boundaries. Of these, four led to amino acid substitutions: Gly328Ser, Asn515Ile, Asp766Gly, and Arg797Gln. When the families were examined, the missense variants co-segregated with VUR (three families) or VUR/CAKUT (one family). These variants were not found in 190 control subjects, and the affected amino acids have been conserved through evolution. In conclusion, a relatively high frequency of ROBO2 variants (5.1%) was found in familial cases; however, functional studies and validation in other cohorts are warranted.

ROBO2 gene variants in children with primary nonsyndromic vesicoureteral reflux with or without renal hypoplasia/dysplasia

“…The first polymorphism, IVS1-53, has been reported previously in patients with VUR or VUR-other CAKUT (9). In this study, this polymorphism was detected in 27 patients (only in heterozygous state) and 71 control subjects (64 in heterozygous and 7 in homozygous state).…”

“…The role of SLIT2-ROBO2 signaling is to restrict GDNF to a single site. In mice, inactivation of either slit2 or robo2 leads to supernumerary ureteric bud development (9,24). The gene codes for two isoforms RΟΒΟ2a and RΟΒΟ2b.…”

“…Recent studies have identified variants of the roundabout, axon guidance receptor, homolog 2 (ROBO2) gene in patients with VUR and VUR accompanied by other CAKUT, but their conclusions are contradictory on whether or not mutations of the ROBO2 gene are a causative factor of VUR or VUR-other CAKUT (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Identification of direct negative cross-talk between the SLIT2 and bone morphogenetic protein–Gremlin signaling pathways

“…The equilibrium dissociation constant (K D ) was derived mathematically from the observed association rate constant (k a ) and the observed dissociation rate constant (k d ). In addition to the mathematically derived K D we also calculated the steady state K D by plotting the concentration of the analyte on the x-axis versus the corresponding RU at equilibrium by guest on May 11, 2018 http://www.jbc.org/ Downloaded from on the y-axis and determining the EC 50 of that curve.…”

“…Disruption of SLIT2-ROBO2 signaling during kidney development can lead to congenital anomalies of the kidney and urinary tract (CAKUT) (14)(15)(16)(17)(18). In adult tissue, the SLIT-ROBO interaction can inhibit nephrininduced actin polymerization and the attachment of glomerular podocytes which are essential for glomerular filtration (19,20), mediate fibroblast activation and fibrotic disease progression (21-24), regulate tumor growth (25-27), and promote angiogenesis (28,29).…”