# Zfp423 Mechanisms in Joubert Syndrome and Related Disorders

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $345,412

## Abstract

Project Summary:
This project focuses on cellular, genetic, and molecular mechanisms that underlie developmental
abnormalities in ZNF423-realted ciliopathy. The ciliopathies comprise a spectrum of disorders unified
by defects in primary cilia. Clinical presentations range from primary involvement of a single organ
(most often hindbrain, kidney, liver or eye) to more severe presentations, such as Meckel syndrome,
with severe and pleiotropic developmental phenotypes in several organs. Several genes have been
identified for ciliopathy disorders, with the overwhelming majority encoding physical components of
primary cilia. Regulatory genes that control cilium-dependent signaling and genetic modifiers that
control the outcome of ciliary defects are only beginning to be tied to pathogenic mechanisms. This
project focuses on the role and mechanisms of ZNF423, a constitutively nuclear transcriptional
regulatory protein mutated in Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) patients.
ZNF423 is thought to comprise an integrative node among several transcriptional complexes that
respond to classical developmental signals. As ZNF423 expression is also developmentally dynamic,
the extent to which phenotypes are cell autonomous, rather than defects in reciprocal intercellular
signaling, remains unclear. Aim 1 will use recently developed genetic tools (MADM) to assess cell
autonomy by creating a simple platform for inducing and marking mitotic clones in situ. Because
patient mutations are individually rare, often found on only one allele, and found in subjects with a
range of presentations, it remains unclear what fraction of patients is attributable to ZNF423 and which
ZNF423 mutations are truly pathogenic. Aim 2 will use genome editing in a sensitive and well-validated
mouse model to test phenotypic effect of patient-derived mutations. It remains unclear whether specific
targets of ZNF423 activity might be able to modulate phenotype. Aim 3 will determine whether
decreasing activity of newly identified ZNF423-repressed genes, whose expression is increased in both
knockdown cell and mutant animals, can improve cilium-dependent functions and emergent
phenotypes in the Zfp423 mouse model.

## Key facts

- **NIH application ID:** 10098072
- **Project number:** 5R01NS097534-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** BRUCE A HAMILTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $345,412
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098072

## Citation

> US National Institutes of Health, RePORTER application 10098072, Zfp423 Mechanisms in Joubert Syndrome and Related Disorders (5R01NS097534-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10098072. Licensed CC0.

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