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1 Human Genetics, McGill Universtiy, Montreal, Canada
2 Pediatrics, McGill Universtiy, Montreal, Canada
3 Human Genetics, GSF-Human Genetics, Neuherberg, Germany
4 Pediatrics, Montreal Children's Hospital, Montreal, Canada
* To whom correspondence should be addressed. E-mail: indra.gupta{at}muhc.mcgill.ca.
Vesico-ureteric reflux is a urinary tract abnormality that affects roughly 1/3rd of patients with Renal-Coloboma syndrome, an autosomal dominant condition caused by a mutation in PAX2. Here we report that a mouse model with an identical mutation, the Pax21Neu+/- mouse, has a 30% incidence of vesico-ureteric reflux. In vesico-ureteric reflux, urine flows retrogradely from the bladder to the ureter and is associated with urinary tract infections, hypertension and renal failure. The propensity to reflux in the Pax21Neu+/- mouse is correlated with a shortened intravesical ureter that has lost its oblique angle of entry into the bladder wall compared to wildtype mice. Normally, the kidney and urinary tract develop from the ureteric bud, which grows from a pre-determined position on the mesonephric duct. In Pax21Neu+/- mice, this position is shifted caudally while surrounding metanephric mesenchyme markers remain unaffected. Mutant offspring from crosses between Pax21Neu+/- and Hoxb7/GFP+/- mice have delayed union of the ureter with the bladder and delayed separation of the ureter from the mesonephric duct. These events are not caused by a change in apoptosis within the developing urinary tract. Our results provide the first evidence that vesico-ureteric reflux may arise from a delay in urinary tract maturation and an explanation for the clinical observation that VUR resolves over time in some affected children.
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