# Genomics of mammalian posterior urethral valves

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $521,396

## Abstract

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.

## Key facts

- **NIH application ID:** 10247469
- **Project number:** 5R01DK115574-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Simone Sanna-Cherchi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $521,396
- **Award type:** 5
- **Project period:** 2017-09-22 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247469

## Citation

> US National Institutes of Health, RePORTER application 10247469, Genomics of mammalian posterior urethral valves (5R01DK115574-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10247469. Licensed CC0.

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