ROBO2 Gene Variants Are Associated with Familial Vesicoureteral Reflux

• Published in: Journal of the American Society of Nephrology Vol. 19; no. 4; pp. 825 - 831
• Main Authors: Bertoli-Avella, Aida M., Conte, Maria Luisa, Punzo, Francesca, de Graaf, Bianca M., Lama, Giuliana, La Manna, Angela, Polito, Cesare, Grassia, Carolina, Nobili, Bruno, Rambaldi, Pier Francesco, Oostra, Ben A., Perrotta, Silverio
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.04.2008; American Society of Nephrology
• Subjects: Adolescent; Adult; Biological and medical sciences; Child; Child, Preschool; Clinical Research; Female; Humans; Infant; Male; Medical sciences; Mutation; Nephrology. Urinary tract diseases; Pedigree; Receptors, Immunologic - genetics; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vesico-Ureteral Reflux - genetics; Variant; Nephrology; Urinary system disease; Genetic variability; Gene; Vesicoureteral reflux; Genotype; Genetics; Bladder disease; Urinary tract disease; Urology
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2007060692

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.