# Cellular and molecular mechanisms underlying DDX3X syndrome

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $678,057

## Abstract

Abstract
 Mutations in DDX3X are strongly associated with autism spectrum disorder (ASD), and may
account for 1-3% of unexplained developmental delay (DD) in females, making this one of the
most common of neurodevelopmental disorders. DDX3X is considered a high confidence ASD
gene by SFARI gene. DDX3X encodes an RNA-binding protein of the DEAD-box helicase family.
While broadly implicated in mRNA metabolism, DDX3X is best characterized as a translational
regulator. Despite the robust link between DDX3X and ASD, virtually nothing is known about
DDX3X function in the developing brain nor the mechanisms by which DDX3X mutations perturb
cellular function. Further, it remains largely unknown how DDX3X impacts neural progenitors and
how it controls translation of its targets. This limits our understanding of the causes of ASD for
this common condition and the potential for therapeutic intervention. Our proposal addresses
these gaps by investigating how DDX3X mutations impair brain development and protein
synthesis. Our preliminary data indicates requirements for DDX3X in neural progenitors and
suggests that translational regulation may be relevant for disease. This has led to our central
hypothesis that DDX3X mutations impair neurogenesis by disrupting the progenitor cell cycle and
translation of key targets. To address this hypothesis we will: Define how DDX3X loss of function
impairs cell fate specification in mouse models, determine how DDX3X missense mutations
impair human neural progenitor function and differentiation, and identify the mechanism(s) by
which genetic variants in DDX3X alter protein synthesis. Our diverse scientific approaches enable
this multifaceted understanding of DDX3X function and developmental role. Upon completion of
this study we will gain fundamental insights into DDX3X biology and guide a framework for
therapeutic intervention.

## Key facts

- **NIH application ID:** 10155248
- **Project number:** 1R01NS120667-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Stephen Nicholas Floor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $678,057
- **Award type:** 1
- **Project period:** 2021-01-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155248

## Citation

> US National Institutes of Health, RePORTER application 10155248, Cellular and molecular mechanisms underlying DDX3X syndrome (1R01NS120667-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10155248. Licensed CC0.

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