Abstract for presentation at 11th International Congress of Human Genetics

Gly691Ser mutation of Ret tyrosine kinase is associated with primary vesicoureteral reflux in the French-Canadian population in Quebec

  • Yaoming Yang, Canada
  • Mr Julien Letendre, Urology Clinic of Sainte-Justine Hospital, Department of Surgery, Faculty of Medicine, University of Montreal, Canada
  • Dr Anne-Marie Houle, Urology Clinic of Sainte-Justine Hospital, Department of Surgery, Faculty of Medicine, University of Montreal, Canada
  • Dr Andrea Richter, Medical Genetics, Sainte-Justine Hospital, Department of Pediatrics, Faculty of Medicine, University of Montreal, Canada

    • Purpose: Primary vesicoureteral reflux (pVUR) is a common congenital urinary tract abnormality in children in which urine flows backward from the bladder to the ureter due to developmental defect at the junction of the ureter and the bladder. Our aim is to use clinically well-characterized pVUR patients to identify responsible gene(s).
    Methods: We recruit only pVUR patients whose grandparents were born in Canada and with French as their mother tongue to maximize the genetic homogeneity. pVUR is diagnosed by a VCUG with other urological malformations being ruled out. Genomic DNA were extracted from patient blood samples. Then interested regions of targeted genes were amplified and sequenced. The resulting sequences were further confirmed and compared with that of the French-Canadian control.
    Results: We have recruited 125 pVUR French-Canadian families in Quebec. We chose receptor tyrosine kinase Ret as one targeted gene because Ret-mediated signaling pathways are known to be required and sufficient to induce ureter development. We have screened the ret gene in 118 pVUR patients and found that 83 patients (71%) were carriers of the single nucleotide polymorphism (SNP) rs1799939, which results in a Gly691Ser mutation. The allelic frequency of the SNP rs1799939 dramatically increased from 0.145 in the control to 0.360 in the patients, which is statistically significant (p<0.001). Similar changes were not observed in 6 other flanking SNPs screened simultaneously. Introducing a Gly691Ser mutation, where the nonpolar glycine is changed to polar and phosphorylatable serine, may induce a change of conformation/electric charge in Ret and thus interfere with the known regulatory functions of the nearby phospho-Tyr687 and -Ser696 on the actin reorganization responsible for cell motility and morphology and consequently lead to a deficiency in ureteral development.
    Conclusions: Gly691Ser mutation of Ret is associated with pVUR in the French-Canadian population in Quebec.

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