# Precision models of ARX-associated neurodevelopmental disorders

> **NIH NIH R01** · UNIVERSITY OF TEXAS SAN ANTONIO · 2020 · $531,135

## Abstract

PROJECT SUMMARY/ABSTRACT
Nearly 1% of the US population suffers from epilepsy (prevalence 5-8.4/1000), with a slightly higher
prevalence in children. Despite this high frequency, the molecular and cellular basis for only a few types
of epilepsy have been defined, while the basis for most remains unknown. Mutations in one gene, ARX,
are of considerable interest as distinct mutations are associated with a spectrum of neurological
disorders with epilepsy representing one of the few consistent features. ARX has 4 poly-alanine (pAla)
tracts and expansions in the 1st or 2nd tract are consistently associated with epilepsy. pAla tract
expansion mutations are a relatively newly described mutation type and are associated with a growing
number of human developmental disorders, epilepsy being a component of several. How this mutation
type results in human disorders and epilepsy in particular are not well understood. Our prior work has
demonstrated that an expansion in the first pAla tract of ARX results in structural change in the protein
and the resulting protein has differential effects on developing cortical interneuron- and projection
neuron progenitor cells. In other studies, we have shown that the loss of Arx from each progenitor
population accounts for specific components of the mouse and human phenotypes. In this multi-PI R01
proposal, building on our data from the past ten years, we seek to unite human stem cell models with
mouse models to elucidate the pathobiology underlying ARX related epilepsy, and specifically the
function of pAla tracts along with mutations in these tracts. Aim 1 will evaluate the cellular impact of
ARX pAla mutations in patient-derived spheroids. Aim 2 will examine the role of ARX pAla mutations
on cortical interneuron migration and network activity. Aim 3 will determine the effects of Arx pAla
expansion mutations on brain development and function. This project will utilize human induced
pluripotent stem cell (hiPSC) and spheroid models and complement these with mouse embryonic stem
cell lines and behavioral and physiological assays in mice. Together, these studies are expected to
provide a greater understanding of how pAla tracts function in normal and abnormal brain development,
contribute to our understanding of the pathogenesis of epilepsy, and generate valuable resources and
mouse models to test potential therapeutic strategies for developmental epilepsies.

## Key facts

- **NIH application ID:** 9939728
- **Project number:** 5R01NS113516-02
- **Recipient organization:** UNIVERSITY OF TEXAS SAN ANTONIO
- **Principal Investigator:** Jeffrey A Golden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $531,135
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939728

## Citation

> US National Institutes of Health, RePORTER application 9939728, Precision models of ARX-associated neurodevelopmental disorders (5R01NS113516-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939728. Licensed CC0.

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