# Role of RNA-binding protein DDX3X in heart development and disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $736,574

## Abstract

PROJECT SUMMARY
The relatively finite number of ~20,000 protein coding genes in the mammalian genome limits the overall diversity
that transcriptional regulation can achieve in a given biological context. This diversity can be enhanced by many
orders of magnitude by post-transcriptional regulation such as alternative splicing and modification and
degradation of mRNA, which in turn leads to a greater protein diversity and thus a greater functional complexity
of the cell. This seems particularly relevant in the context of complex processes such as cell specification and
organogenesis. The importance of RNA regulation is further supported by the large number RNA-binding
proteins encoded in the human genome (~1,500) and their ever more prominent emergence in the context of
disease. Despite the clear evidence of the relevance of RNA regulation, much less remains known compared to
the exceptionally well-researched gene regulatory mechanisms. This lack of progress is in part due to technical
challenges associated with studying and manipulating RNA, particularly during early development. However,
recent advancements in this area now afford new opportunities to broaden our knowledge in these critical
regulatory mechanisms and start to fill this critical knowledge gap. Here we will interrogate RNA-binding proteins
important for cardiac development, specifically the the X-linked protein DDX3X. Mutations in DDX3X lead to
DDX3X Syndrome, which is characterized by intellectual disability, autism spectrum disorder, congenital brain
malformations and motor problems. DDX3X has not been interrogated during cardiogenesis to date, but recent
studies have uncovered that individuals with DDX3X Syndrome frequently present with congenital heart disease.
Based on our preliminary findings we hypothesize that DDX3X acts in a spatio-temporal manner, by targeting
distinct regulatory networks during the development of the different cell types of the heart. We further hypothesize
that disease-causing mutations in DDX3X affect cellular dysfunction by specific mechanisms of DDX3X target
regulation. Aim 1 will uncover the direct, and functionally relevant targets of DDX3X. Aim 2 will determine the
cellular phenotype of DDX3X-deficient male and female embryos. Aim 3 will elucidate genotype-phenotype
correlations in DDX3X Syndrome patient-derived hPSC-CMs. Successful completion of the aims are expected
to identify and characterize the cellular requirements and in depth molecular mechanisms of DDX3X, a new
RNA-binding protein that we found to be essential for heart development. The overall and long-term goal is to
contribute to a better understanding of RNA regulatory mechanisms, specifically during cardiac development
and in the context of the formation of congenital heart disease.

## Key facts

- **NIH application ID:** 10944661
- **Project number:** 1R01HL175488-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Nicole Dubois
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $736,574
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10944661

## Citation

> US National Institutes of Health, RePORTER application 10944661, Role of RNA-binding protein DDX3X in heart development and disease (1R01HL175488-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10944661. Licensed CC0.

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