# Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction.

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2021 · $169,440

## Abstract

PROJECT SUMMARY
Title: Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction
 Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic
kidney disease in childhood. Over 40 monogenic etiologies of CAKUT have been identified, and another 150
genes have been described to cause syndromes in which urinary tract malformations are an integral
component. However, the majority of these genes coalesce into pathways that regulate upper urinary tract
development, such as metanephric mesenchyme transition and ureteric bud formation. The pathogenesis and
genetic regulation of lower urinary tract disease remain poorly understood. Recently, through the use of whole
exome sequencing, I identified mutations in the α3-subunit of the nicotinic acetylcholine receptor, CHRNA3, as
a novel cause of bladder dysfunction with secondary CAKUT. This is one of just eight known monogenic
causes of congenital bladder dysfunction, and, uniquely, is a gene that regulates autonomic nervous system
function. I hypothesize that additional monogenic causes of lower urinary tract disease can be identified
through the use of whole exome sequencing, and additionally, that these genes will coalesce upon
pathways that regulate urothelial signaling, detrusor contraction, and bladder innervation.
 The aims of the proposed research are twofold: (1) to apply both a candidate gene and unbiased analysis
strategy to whole exome sequencing data in order to discover novel monogenic causes of bladder dysfunction
and (2) to apply an integrated genomic approach using whole exome and whole transcriptome sequencing to
an international cohort of children with CAKUT. Accomplishment of the proposed research above will provide
additional insight into the pathomechanisms that govern bladder development and function, and, ultimately,
could lead to novel therapeutic strategies for children with bladder dysfunction. In addition, validation of a
method for urinary transcriptome sequencing can help to overcome current limitations in whole exome
sequencing in the identification and interpretation of splice-altering genetic variants.
 This K08 application encompasses a comprehensive career development plan to not only ensure progress
and success in carrying out the proposed research, but also to facilitate my transition to an independent
investigator. It encompasses regular meetings with my mentor and advisory committee, research and career
development seminars, courses in genomics and transcriptomics, and participation at national and
international conferences. The research will be conducted in the rich academic environment at Boston
Children's Hospital and Harvard Medical School, which provides an ideal environment for further training and
career development.

## Key facts

- **NIH application ID:** 10104150
- **Project number:** 1K08DK127011-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Nina Mann
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,440
- **Award type:** 1
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104150

## Citation

> US National Institutes of Health, RePORTER application 10104150, Discovery and pathogenic characterization of novel monogenic causes of bladder dysfunction. (1K08DK127011-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10104150. Licensed CC0.

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