# Genetic and Molecular Etiology of Developmental Kidney and Urinary Tract Abnormalities in the DiGeorge, or 22q11.2, Syndrome.

> **NIH NIH F32** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $72,960

## Abstract

PROJECT SUMMARY
 Up to 50% of worldwide cases of pediatric end-stage kidney failure fall within the spectrum of
congenital anomalies of the kidney and urinary tract (CAKUT). Although the genetic bases of CAKUT remain
elusive, recent human studies are starting to shed light into the pathogenesis of disease. Studies from our
group using a combination of family-based as well as case-control analyses coupled to functional modeling in
vertebrates have identified multiple genes that, when mutated in humans, lead to CAKUT. Interestingly,
CAKUT phenotypes are described in ~30% of patients with DiGeorge Syndrome, and deletions on
chromosome 22q11.2 are the most common cause of DiGeorge syndrome, constituting the most common
microdeletion syndrome in humans. To date, our work has shown that haploinsufficiency and point mutations in
CRKL, one of the genes found at the 22q11.2 locus, drive kidney and urinary tract malformations in DiGeorge
syndrome and sporadic CAKUT; however, the causal mechanisms of human disease occur are still unknown.
 In both in mice and humans, CRKL exists as at least two main transcripts isoforms, raising the
possibility of a complex regulation of CRKL and its binding partner(s) in regulating kidney and urinary tract
development. Although some animal studies have shown that manipulation of Crkl in the mouse can lead to
kidney phenotypes, none have addressed the role of different Crkl isoforms. This leaves unanswered
questions of how each variant is involved and what tissue- and cell-specific roles they play in the modulation of
developmental signaling cascades. In an attempt to answer these questions, we devised a multidisciplinary
approach that makes use of several mouse models, where one or both transcripts will be genetically ablated in
a tissue-specific manner. The experiments proposed herein therefore test the central hypothesis that the
two isoforms of Crkl differentially regulate specific events of kidney and urinary tract development,
either independently of one another or by modulating the activity of each other. My main goal is to
discover how different isoforms of the same gene can have multifaceted effects on the development of the
kidney and urinary tract. In Aims 1 and 2, I will address key questions concerning the precise spatiotemporal,
and potentially differential, expression pattern of each splice variant, the developmental role of each transcript
in the kidney (Aim 1) and urinary tract (Aim 2), and the developmental requirements of one isoform over
another. In Aim 3, traditional and transcriptomic/RNAseq approaches will be used to identify key
developmental signaling cascades that are affected by the loss of each Crkl isoform in vivo, with findings
verified through biochemical and histochemical assays. Ultimately, through the use of developmental genetics
and computational approaches to design a novel analytical framework that integrates phenotypic, genetic and
single-cell transcriptomic data, I intend to, a) refin...

## Key facts

- **NIH application ID:** 9906751
- **Project number:** 5F32DK121454-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jeremiah Martino
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $72,960
- **Award type:** 5
- **Project period:** 2019-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906751

## Citation

> US National Institutes of Health, RePORTER application 9906751, Genetic and Molecular Etiology of Developmental Kidney and Urinary Tract Abnormalities in the DiGeorge, or 22q11.2, Syndrome. (5F32DK121454-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9906751. Licensed CC0.

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