# Identifying the RNA Splicing and Gene Expression Changes that cause Congenital Myotonic Dystrophy

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $497,138

## Abstract

Abstract
 Congenital myotonic dystrophy, the most severe form of myotonic dystrophy, causes
weakness, breathing problems, and feeding problems at birth. During childhood, children often
have intellectual impairment, fatigue, behavioral concerns and weakness. Importantly, many of
the symptoms are distinct from those adults with myotonic dystrophy. In adults with myotonic
dystrophy, a toxic RNA repeat expansion leads to global misregulation of RNA splicing. It is not
clear if the same mechanism is involved in congenital myotonic dystrophy. Such information is
critical since new treatments for myotonic dystrophy target this issue. This proposal is designed
to evaluate the pathogenesis of congenital myotonic dystrophy. The investigators will evaluate
changes in RNA splicing and gene expression in muscle samples and then validate these
changes in a DM1 cell model by enrolling 100 children below the age of 15 with congenital
myotonic dystrophy. Children will be evaluated with measures of physical function and
cognition at the baseline visit and a fine needle aspirate of the muscle will be collected. Children
with congenital myotonic dystrophy will return for a clinical evaluation at 12 months. These
children will be compared to 30 histopathologically normal muscle biopsies.
 In Aim 1, we will initially evaluate changes in RNA splicing and correlate these with the
clinical outcome measures to identify those specific transcripts that most directly correlate with
symptoms. Key RNA splicing events will be evaluated as predictors of clinical function at the
12-month visit. In Aim 2, we will also evaluate secondary gene expression changes in a similar
manner, which has not been done in myotonic dystrophy. Once key gene expression and RNA
splicing signatures have been identified, Aim 3 will evaluate them in a DM1 cell model to assess
the role of MBNL1 sequestration and other splicing regulators for a particular splice event. This
is a key pathogenic mechanism in DM1. At the completion of this project, we will have identified
key biomarkers and performed preliminary experiments to understand the role of these events
in the mechanism of disease. By better understanding the pathogenesis of congenital myotonic
dystrophy, we allow these children access to disease modifying therapies in myotonic
dystrophy, as well as identify new therapeutic targets for drug development.

## Key facts

- **NIH application ID:** 10402925
- **Project number:** 5R01NS104010-06
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Nicholas Elwood Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $497,138
- **Award type:** 5
- **Project period:** 2018-12-19 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402925

## Citation

> US National Institutes of Health, RePORTER application 10402925, Identifying the RNA Splicing and Gene Expression Changes that cause Congenital Myotonic Dystrophy (5R01NS104010-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10402925. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*