# Molecular Characterization of Joubert Syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $510,012

## Abstract

Project Summary
Congenital ataxia presents in early childhood with non-progressive hypotonia, gross motor, fine
motor and cognitive delays. These disorders are distinct from the progressive ataxias because of
the presence of congenital cerebellar malformations and because they are typically inherited
recessively. Joubert Syndrome and Related Disorders (JSRD) constitute a major subset of these
conditions, consisting of a cerebellar midline (vermis) malformation, a nearly pathognomonic Molar
Tooth sign on brain Imaging (MTI) and co-existent oculomotor apraxia and episodic breathing
dysrhythmias. In our published data, we have: 1] Identified ten unique genetic causes of JSRD
(nearly half of the published causes), 2] Generated genotype-phenotype correlations involving
cerebellar, retinal, renal, hepatic, digit, and cerebral manifestations. 3] Identified common founder
mutations that allow for population-based screening. 4] Discovered that JSRD encoded proteins
frequently localize to the cilium. 5] Identified ciliary transition zone (TZ) defects in cells with JSRD
mutations. 6] Performed siRNA cell-based screens for defective ciliogenesis to prioritize candidate
JSRD genes. 7] Generated and characterized multiple zebrafish, mouse and human cell culture
models for JSRD. 8] Defined the concept of ‘Ciliary localization’ model, in which one JSRD gene is
required for ciliary localization of other JSRD proteins. In our unpublished data we have: 1]
Recruited an additional 200 JSRD patients without molecular diagnosis. 2] Performed whole exome
(WES) and whole genome sequencing (WGS) on an additional 100 JSRD families. 3] Identified an
additional 12 novel likely JSRD candidate genes. 4] Generated IPSCs and cerebellar organoids
from mutation-positive and negative families to aid in functional analysis and gene discovery using
RNAseq. 5] Begun functional validation of the putative mutations. 6] Developed methods to
interrogate ciliary structure in a high-throughput fashion with electron microscopy (EM). The goal of
this competing renewal is to identify the remaining ‘discoverable’ genes that lead to JSRD when
lost, functionally validate mutations within the pathogenetic framework, and test the hypothesis that
mutations in JSRD genes lead to collapse of the ciliary TZ. Because the majority of patients still
have unknown cause of disease, this renewal aims to advance knowledge through molecular
characterization of new genes, using newly evolving high-throughput techniques, integrated
bioinformatics, and a unique resource of consanguineous families recruited world-wide. We further
aim to validate these mutations in patient cells, within a mechanistic framework that JSRD genes
are required for essential ciliary structural components during cerebellar development.

## Key facts

- **NIH application ID:** 9988508
- **Project number:** 5R01NS048453-15
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** JOSEPH G GLEESON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $510,012
- **Award type:** 5
- **Project period:** 2004-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988508

## Citation

> US National Institutes of Health, RePORTER application 9988508, Molecular Characterization of Joubert Syndrome (5R01NS048453-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9988508. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*