Communicated by Michael Dean
Primary vesicoureteral reflux (pVUR) is a common, genetically heterogeneous congenital urinary tract abnormality in children. It causes urine to flow backward from the bladder to the ureter due to a developmental defect at the vesicoureteral junction, whose formation requires rearrangement during transformation (Ret)mediated signaling pathways. To study the genetic causes of pVUR in Quebec patients, we used a sequencingbased candidate gene approach to screen the RET gene and found that 83 out of 118 pVUR patients are carriers of the rare A allele of single nucleotide polymorphism (SNP) rs1799939:G4A that results in a Gly691Ser mutation, a statistically significant increase in allelic frequency, that is absent at six flanking RET SNPs tested.
Ser691 is a predicted phosphorylation site and our analysis of transfected cells showed that the Gly691Ser Ret mutant can efficiently interact and associate with a 75-80-kD tyrosine phosphorylated cellular protein, an event not seen with wild-type Ret. This interaction and/or the steric or electric hindrance created by phospho-Ser691 may interfere with the known regulatory functions of the normally phosphorylated phospho-Tyr687 and phospho-Ser696 on the cytoskeleton actin reorganization that are responsible for cell motility and morphology, which consequently may lead to the deficiency in ureteral development observed in pVUR. Our study demonstrates that the Ret Gly691Ser mutation is associated with pVUR and may be one of the genetic causes of this condition in the French-Canadian population in Quebec. Hum Mutat 29(5), 695-702, 2008.