# Molecular Characterization of Pontocerebellar Hypoplasia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $448,569

## Abstract

Project Summary/Abstract
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive pediatric
neurodevelopmental/neurodegenerative disorders, characterized clinically by severe age-dependent
neurological impairment, and notable radiographic volume loss of the pons and cerebellum. Currently there
are 10 partially overlapping subtypes and 13 genes known mutated in PCH, but most cases remain without
genetic diagnosis, suggesting new causes remain to be identified. Several of the genes are implicated in
protein synthesis including key steps of tRNA maturation, mRNA splicing, protein translation and apoptosis,
but fundamental questions remain: 1] How many genetic subtypes remain to be discovered? 2] Why do these
mutations predispose to neuropathology? 3] Can we effect new treatments for these disorders? Through an
international recruitment effort, we have ascertained a cohort of 190 families with recessive PCH and have
begun sequencing to identify new causes and mechanisms. Our preliminary data suggests new treatments
may emerge from these studies. In our preliminary data we have: 1] Recruited a cohort of 190 PCH probands,
including 124 still without cause identified. 2] Identified mutations in AMPD2 associated with a syndromic form
of PCH, leading to GTP depletion and subsequent collapse of protein synthesis. 3] Identified a common
founder mutation in CLP1 leading to defective assembly of the tRNA splicing machinery. 4] Identified mutations
in TOE1 as the long-sought snRNA 3'-exonuclease, leading to defective mRNA splicing. 5] Identified mutations
in several other genes encoding tRNA processing factors. 6] Identified mutations in PPIL1 predicted to lead
to defective mRNA splicing. 7] Uncovered a total of 13 new genetic causes of PCH, more than doubling the
number of known causes. These novel PCH candidate genes are mutated in patients with unique presenting
features, highlighting new genotype-phenotype correlations, emphasizing the protein synthetic defect model
and pointing to new mechanisms of disease. The goal of this application is to identify the remaining
`discoverable' genes that when mutated lead to PCH, functionally validate mutations within a pathogenic
framework, and test the hypothesis that mutations in PCH genes lead to collapse of protein synthesis and
vulnerability to apoptosis.

## Key facts

- **NIH application ID:** 9948024
- **Project number:** 5R01NS098004-05
- **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:** $448,569
- **Award type:** 5
- **Project period:** 2016-08-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948024

## Citation

> US National Institutes of Health, RePORTER application 9948024, Molecular Characterization of Pontocerebellar Hypoplasia (5R01NS098004-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9948024. Licensed CC0.

---

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