Mutations in the ROBO2 and SLIT2 genes are rare causes of familial vesico-ureteral reflux

Abstract

Familial clustering of vesico-ureteral reflux (VUR) suggests that genetic factors play an important role in the pathogenesis of this condition. The SLIT2 protein and its receptor, ROBO2, have key functions in the formation of the ureteric bud. Two recent studies have found that ROBO2 gene missense mutations are associated with VUR. In the study reported here, we investigated the genetic contribution of the SLIT2 and ROBO2 genes in non-syndromic familial VUR by mutation screening of 54 unrelated patients with primary VUR. Direct sequencing of all 26 exons and the exon-intron boundaries revealed six ROBO2 gene variants, two of which were new. Direct sequencing of all 37 exons and the exon-intron boundaries identified 20 SLIT2 gene variants, two of which were new. One variant, c.4253C > T, which was found in two families, leads to an amino acid substitution in a relatively well-conserved amino acid, p.Ala1418Val, which was predicted to cause an altered secondary structure but to have little impact on the three-dimensional structure. This missense variant did not segregate with VUR in these two families and was not found in 96 control subjects. We conclude that gene variants in ROBO2 and SLIT2 are rare causes of VUR in humans. Our results provide further evidence for the genetic heterogeneity of this disorder.

Genes in the Ureteric Budding Pathway: Association Study on Vesico-Ureteral Reflux Patients

“…[43] ROBO2 was shown to be mutated in a small number of (familial) VUR/CAKUT patients. [23], [29], [45] Mutations in UPK3A are a cause for renal adysplasia, a phenotype within the CAKUT spectrum. [46], [47] Mouse models for all four genes show phenotypes reminiscent of VUR/CAKUT.…”

“…[26], [27] ROBO2 (ENSG00000185008) regulates the expression of GDNF [28] and was shown to be mutated in a small number of VUR/CAKUT patients. [29] Genes involved in the RET/GDNF pathway are obvious functional candidate genes for VUR. Genes involved in syndromal VUR, like EYA1 in Branchiootorenal Syndrome (MIM 113650) and PAX2 in Papillorenal Syndrome (MIM 167409), are often also implicated in the ureteric budding pathway and thus attractive candidate genes as well.…”

Genetics of congenital anomalies of the kidney and urinary tract

“…For example, despite severe renal phenotype observed in ROBO2/SLIT2-mutant mice, which includes formation of supernumerary ureters [44], these gene mutations are very rarely associated with familial nonsyndromic VUR in children [71,72]. Similarly, mutations in homeobox A11 and D11(HoxA11/HoxD11), which cause renal hypoplasia in mice [73], are not associated with CAKUT in children [74].…”

Genetics of vesicoureteral reflux

“…24,105,106 roBo2/sliT2 to date, two groups have reported ROBO2 gene missense mutations associated with vur, 107,108 and a further study has supported the hypothesis that variations in ROBO2 and SLIT2 are rare causes of vur in humans. 109 However, subsequent candidate gene linkage studies including the ROBO2 locus found no evidence for linkage, 23 and similar study has found no evidence of linkage at SLIT2. 24 …”