# Genetic and epigenetic mechanisms of FSHD pathogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $505,724

## Abstract

Abstract
Facioscapulohumeral dystrophy (FSHD) is one of the most common muscular dystrophies in the U.S.
Currently, there is no effective treatment, and the pathogenic process is still not completely understood. Most
cases (>95%) of FSHD involve mono-allelic deletion of macrosatellite D4Z4 repeat sequences at the
subtelomeric region of chromosome 4q (FSHD1), while the remaining ~5% of cases demonstrate no D4Z4
repeat contraction (FSHD2). Mutations in the SMCHD1 genes were linked to FSHD2, and also greatly
exacerbate the phenotype of FSHD1 by acting as a modifier of the disease severity. Expression of the DUX4
gene encoded within the D4Z4 repeat is critically linked to the development of FSHD. Since overexpression of
DUX4 is cytotoxic in human myocytes and mice, it is thought that DUX4-induced cytotoxicity is the cause of
dystrophy. However, only ~0.1% of patient muscle cells appear to express DUX4, and DUX4 expression can
occasionally be observed in muscle cells from unaffected individuals. It is not straightforward to study FSHD in
model organisms as D4Z4 repeats and some of the critical DUX4 target genes are primate-specific. During the
previous funding period, we found evidence that DUX4-negative patient myocytes exhibit altered gene
expression distinct from control myocytes and cross-regulation of DUX4 target transcription factors contributing
to sustaining the DUX4 gene network. These findings strongly argue that FSHD mechanism is not simply
DUX4-induced cell killing and further investigation is necessary to understand FSHD pathogenesis. We also
developed genetically engineered mutant myoblast lines carrying D4Z4 deletion, SMCHD1 mutation or both to
simulate FSHD1, FSHD2 and severe cases of FSHD1, respectively and began to characterize epigenetic and
gene expression consequences of defined mutations in the isogenic background. Specific Aims of this project
are (1) to create additional mutant clones to interrogate the consequences of FSHD mutations in different
muscles with different disease susceptibility and during early myogenesis; (2) to investigate dynamics and
regulation of DUX4 and target gene expression, and (3) to identify a modifier gene(s) that dictates disease
susceptibility and severity. The successful outcome of the project should reveal DUX4 and target gene
dynamics and their contributions to FSHD pathogenesis and identify critical determinants for the disease
susceptibility, which may lead to identification of potentially new therapeutic targets.

## Key facts

- **NIH application ID:** 10695049
- **Project number:** 5R01AR071287-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Seyed Ali Mortazavi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $505,724
- **Award type:** 5
- **Project period:** 2017-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10695049

## Citation

> US National Institutes of Health, RePORTER application 10695049, Genetic and epigenetic mechanisms of FSHD pathogenesis (5R01AR071287-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10695049. Licensed CC0.

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