# Identifying the RNA Splicing and Gene Expression Changes that Cause Congenital Myotonic Dystrophy (Renewal)

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $619,566

## Abstract

Abstract
 Congenital myotonic dystrophy (CDM), the most severe form of myotonic dystrophy, causes muscle
weakness, breathing problems, and feeding difficulties at birth. During childhood affected individuals
experience intellectual impairment and gastrointestinal issues while, in contrast, muscle strength and
weakness improve. Muscle symptoms associated with adults with myotonic dystrophy, including myotonia and
fatigue, are not observed until individuals reach adolescence. In the previous proposal period, the investigators
clinically defined this triphasic pattern of motor involvement via enrollment of over 100 children in a
comprehensive clinical study to evaluate measures of physical function over 12 months.
 In adults with myotonic dystrophy, a toxic RNA repeat expansion leads to global dysregulation of RNA
splicing. Within the previous proposal period we performed RNA sequencing on 36 congenital myotonic
dystrophy muscle biopsies from individuals 2 weeks to 16 years of age. We found that the severity of RNA mis-
splicing mirrored the triphasic course of muscle symptoms captured clinically; children in early childhood
showed improvement in RNA splicing dysregulation that regressed in adolescence. This result was bolstered
by the inclusion of biopsies sampled from individuals at two ages across development. While these
observations correlate with the clinical course of CDM, the mechanisms responsible for these dynamic shifts in
mis-splicing remain unknown. This proposal is designed further clarify and define the molecular mechanisms
responsible for the clinical and molecular progression of CDM.
 In Aim 1, we will enroll additional children with CDM that have acquired a previous muscle biopsy in a
clinical follow-up study to acquire both longitudinal assessments of muscle function and a secondary muscle
biopsy. RNA sequencing will be performed and mis-splicing and gene expression quantified to validate the
course of CDM disease pathogenesis. In Aim 2 and 3, we will evaluate two potential molecular mechanisms
based on our prior data that may contribute to the complex trajectory of CDM disease. In Aim 2, we will define
the proliferative and regenerative capacity of CDM muscle stem cells across pediatric development and the
contribution mediated via the IGF2 mitogenic signaling axis. In Aim 3, we will define how expression of core
spliceosomal patterns contribute to the unique mis-splicing signatures observed within cohorts of CDM
individuals. At the completion of this project, we will have validated the clinical and molecular course of CDM
disease progression across pediatric development and performed experiments vital to understanding the
mechanisms that contribute to this dynamic pattern. By better understanding the pathogenesis of CDM, we
both allow access of these children to forthcoming disease modifying therapies in myotonic dystrophy, as well
as, identify new therapeutic targets for drug development.

## Key facts

- **NIH application ID:** 10882023
- **Project number:** 2R01NS104010-07A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Nicholas Elwood Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $619,566
- **Award type:** 2
- **Project period:** 2018-04-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882023

## Citation

> US National Institutes of Health, RePORTER application 10882023, Identifying the RNA Splicing and Gene Expression Changes that Cause Congenital Myotonic Dystrophy (Renewal) (2R01NS104010-07A1). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10882023. Licensed CC0.

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