# Zfp423 Mechanisms in Joubert Syndrome and Related Disorders

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $555,517

## Abstract

Project Summary:
This project develops cell and animal models to understand the role of a multivalent transcription factor,
ZNF423, in integrating information from extracellular signaling and intracellular lineage pathways during
hindbrain development. ZNF423 encodes a constitutively nuclear transcriptional regulatory protein that
binds lineage differentiation factors of the EBF family and transcriptional effectors for canonical signling
pathways, including SMAD, retinoic acid, and NOTCH intracellular domains. ZNF423 mutations are
reported in rare Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) ciliopathy patients. The
ciliopathies comprise a broad family of individually rare disorders unified by signaling defects in
primary cilia. Clinical presentations range mild to lethal and from primary involvement of a single organ
to more pleiotropic presentations. The overwhelming majority of genes identified for ciliopathy disorders
encode physical components of primary cilia. Regulatory genes that control cilium-dependent
signaling and genetic modifiers that change the outcome of ciliary defects remain understudied with
respect to pathogenic mechanisms and potential points for intervention in more typical cases.
ZNF423 is thought to comprise an integrative node among several transcriptional complexes that
respond to classical intercellular signals during brain development and to regulate SHH signaling
through the primary cilium. Both reported patients and mouse models show hindbrain malformations
that include hypoplasia or agenesis of the vermis. Aim 1 will test hypotheses for ZNF423 activity in
canalizing information from complex signaling environments into predictable cell responses. Aim 2 will
comprehensively test for modifier genes that alter cellular outcomes ex vivo in response to loss of
ZNF423. Aim 3 will test hypotheses for ZNF423 participation in oligogenic brain malformations in a
well-validated animal model.

## Key facts

- **NIH application ID:** 10620800
- **Project number:** 5R01NS097534-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** BRUCE A HAMILTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $555,517
- **Award type:** 5
- **Project period:** 2017-02-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620800

## Citation

> US National Institutes of Health, RePORTER application 10620800, Zfp423 Mechanisms in Joubert Syndrome and Related Disorders (5R01NS097534-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10620800. Licensed CC0.

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