Genetics of Congenital Obstructive Uropathy

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DESCRIPTION (provided by applicant): Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) account for 40-50% of pediatric end-stage kidney failure worldwide. Among CAKUT categories, congenital obstructive uropathy represents a common and severe form of malformation. Congenital hydronephrosis is the most frequent anomaly of the urinary tract detected by prenatal ultrasound, occurring in up to 2% of normal pregnancies. Congenital obstructive uropathy can occur as familial or sporadic disease with highly variable phenotypic expression. Due to paucity of fundamental insight about primary pathogenesis, diagnostic and therapeutic options are severely limited. We recently implemented whole exome sequencing combined to functional modeling in zebrafish to identify dominant mutations in DSTYK in up to 2.3% of patients with congenital obstructive uropathy and associated urinary tract malformations (Sanna-Cherchi et al, New Engl J Med 2013). The protein encoded by DSTYK acts as a positive regulator of fibroblast growth factor (FGF) signaling during nephrogenesis. This study illustrates the power of combining whole exome sequencing with functional modeling in animal models to identify novel disease causing mutations in traits characterized by high genetic heterogeneity, incomplete penetrance, variable phenotypic expression, and small/medium pedigree size. Here we propose to characterize the function of DSTYK during embryonic development and nephrogenesis in cell cultures and in mouse models harboring Dstyk mutations, to extend our gene identification effort to 50 additional families with autosomal dominant congenital obstructive uropathy and to perform functional modeling in zebrafish to identify novel susceptibility genes. This study will provide insight into the pathogenesis of congenital obstructive uropathy in humans and animal models and will help develop new diagnostic and therapeutic strategies.