Posterior urethral valves (PUV) are the major cause of lower urinary tract obstruction in male children and account for 17% of pediatric end-stage renal disease. Despite the severity of the disease and its impact on mortality and morbidity, the molecular basis of this condition is largely unknown, resulting in suboptimal diagnostic and therapeutic strategies. The epidemiology of the disease, characterized by high selective pressure versus a phenotype with low fitness, suggests that dominant de novo mutations or recessive inheritance play a major role in disease determination. This proposal represents the natural continuation of a Pilot project from our O'Brien Center of Urology and aims at the identification of the genetic susceptibility factors for posterior urethral valves (PUV). Our central hypothesis is that rare variants with large effect size on the phenotype underlie the genetic architecture of PUV, and that combining high-throughput genomic studies with analysis of two mouse models of disease will lead to the identification of novel disease genes. Our preliminary data using exome and geneome sequencing, CNV analysis, and functional modeling in vertebrate strongly indicate that we can successfully identify novel genomic variants with large effect size, even in scenario of complex genetic architecture and high genetic heterogeneity. In particular, by studying CNVs in a large cohort of PUV patient, we identified different novel candidate genes for PUV and lower urinary tract malformation. We next demonstrated that mouse transcript dosage of one of these gene candidates, Tbx6, results in highly penetrant maldevelopment and lack of canalization of urethra similar to human PUV. Simultaneously, we have identified a set of genes that are disregulated in mouse mutants lacking Sall1, a transcription factor that when mutated in humans causes Townes-Brocks Syndrome (TBS), a clinical entity characterized by different malformations, including anorectal defects, PUV, and hypospadias. We now propose to extend our sequencing effort to additional 200 PUV trios, and to replicate findings in a large cohort of patients to identify novel genes. We will also characterize the lower urinary tract defects of Sall1 and Tbx6 and generate whole transcriptome datasets to identify downstream targets and facilitate gene identification in humans. This study is designed to solve the molecular etiology of PUV, to improve diagnosis and individualized care for children affected by this severe condition, and to identify pathways that can be amenable to therapeutic interventions.

Posterior urethral valves (PUV) are the major cause of lower urinary tract obstruction in male children and account for 17% of pediatric end-stage renal disease. Despite the severity of the disease and its impact on mortality and morbidity, the molecular basis of this condition is largely unknown, resulting in suboptimal diagnostic and therapeutic strategies. Here we propose to use human genetics and mouse models to solve the genetic architecture of this disease.