# D4Z4 Coding Transcripts and FSHD

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2022 · $442,337

## Abstract

PROJECT SUMMARY
Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of the embryonic transcription factor
DUX4 in skeletal muscle. A major mechanism of DUX4-induced cell toxicity in FSHD muscle is through the
transcription of the HSATII pericentromeric repeats and their formation of single and double-stranded
intranuclear ribonucleoprotein (RNP) complexes. In this proposal, we will determine the molecular components
the RNP complexes and mechanisms of their cell toxicity. The significance of this proposal is that it will
establish mechanisms of DUX4-induced pathology in FSHD muscle that will support future therapeutic
interventions. The long-term goal of this project is to establish the mechanisms of DUX4-induced pathology in
FSHD muscle. The overall hypothesis is that expression of DUX4 in FSHD muscle results in the
accumulation of stable RNP complexes that alter the post-transcriptional regulation of other cellular RNAs and
modulates the innate immune response pathways to inhibit the normal response to double-stranded RNAs.
The specific aims of the proposal are: (Aim 1) Determine the RNAs and the proteins that comprise the
intranuclear ribonucleoprotein complexes and their contribution to cell toxicity and genome instability. (Aim 2)
Determine whether DUX4 regulates the selective degradation or translation of specific subsets of mRNAs.
(Aim 3) Test the hypothesis that interactions between DUX4 and components of the innate immune response
pathway represent a conserved function to modulate ISG induction by dsRNAs. Together, these aims will
further establish the molecular basis of FSHD pathophysiology and identify new opportunities for future
therapies.

## Key facts

- **NIH application ID:** 10656143
- **Project number:** 6R01AR045203-23
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Stephen J Tapscott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $442,337
- **Award type:** 6
- **Project period:** 1998-09-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656143

## Citation

> US National Institutes of Health, RePORTER application 10656143, D4Z4 Coding Transcripts and FSHD (6R01AR045203-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10656143. Licensed CC0.

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