title: 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 = 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.
authors.affiliation: Department of Clinical Genetics, Erasmus MC Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. a.bertoliavella@erasmusmc.nl.
authors.forename: Aida M
authors.initials: AM
authors.lastname: Bertoli-Avella
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Conte
authors.forename: Francesca
authors.initials: F
authors.lastname: Punzo
authors.forename: Bianca M
authors.initials: BM
authors.lastname: de Graaf
authors.forename: Giuliana
authors.initials: G
authors.lastname: Lama
authors.forename: Angela
authors.initials: A
authors.lastname: La Manna
authors.forename: Cesare
authors.initials: C
authors.lastname: Polito
authors.forename: Carolina
authors.initials: C
authors.lastname: Grassia
authors.forename: Bruno
authors.initials: B
authors.lastname: Nobili
authors.forename: Pier Francesco
authors.initials: PF
authors.lastname: Rambaldi
authors.forename: Ben A
authors.initials: BA
authors.lastname: Oostra
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D011971:Receptors, Immunologic / Q000235:genetics*; D014718:Vesico-Ureteral Reflux / Q000235:genetics*; D000097905:Roundabout Proteins
chemical_list: D011971:Receptors, Immunologic; C498890:ROBO2 protein, human; D000097905:Roundabout Proteins