# Identifying the molecular mechanisms of GEMIN5 mutations in a novel cerebellar ataxia syndrome

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $523,554

## Abstract

Abstract
GEMIN5, an RNA-binding protein, is essential for assembly of the Survival Motor Neuron (SMN)
complex. GEMIN5 facilitates the formation of small nuclear ribonucleoproteins (snRNPs; the
building blocks of spliceosomes). We identified novel autosomal recessive variants in the
GEMIN5 gene in multiple patients presenting with motor dysfunction, ataxia, and cerebellar
atrophy.
Our proposed studies are aimed to understand the molecular mechanisms of mutant GEMIN5
responsible for causing the neurological abnormalities in our patients. We found that patient a
significant decrease in GEMIN5 protein levels and reduced protein stability in patient iPSC
neurons suggesting a possible loss of function mechanism. Our in vitro assembly assay
showed that GEMIN5 variants perturb snRNP assembly formation. To understand the
consequences of loss of function GEMIN5, we knockdown endogenous rigor mortis, the
Drosophila homologue of human GEMIN5, in Drosophila. Knockdown of rigor mortis (rig)
caused motor dysfunction, reduced life span and developmental delay. Interestingly, we
observed that CoQ10 levels were significantly reduced in human patient cells and our
drosophila model. Treatment with CoQ10 reduced the disease course in human GEMIN5
patients. We generated a mouse model of Gemin5 using CRISPR/cas9 and found early lethality
in mice. Our proposed studies are aimed to understand the molecular mechanisms of GEMIN5
by 1) conducting functional analysis of mutant GEMIN5 patient neurons; 2) examining if
GEMIN5 variants cause mitochondrial dysfunctions in vivo and iPSC neurons; and 3)
investigating the mechanisms of GEMIN5 mutations in mouse models. We expect to identify the
molecular pathways that are perturbed in human patients.

## Key facts

- **NIH application ID:** 10930099
- **Project number:** 5R01NS134215-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Udai B Pandey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $523,554
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930099

## Citation

> US National Institutes of Health, RePORTER application 10930099, Identifying the molecular mechanisms of GEMIN5 mutations in a novel cerebellar ataxia syndrome (5R01NS134215-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10930099. Licensed CC0.

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