# Single-cell splicing analysis of the heart in myotonic dystrophy

> **NIH NIH F32** · STANFORD UNIVERSITY · 2020 · $65,310

## Abstract

PROJECT SUMMARY/ABSTRACT
 Myotonic dystrophy type 1 (DM1) is a highly variable genetic disease with unpredictable manifestation,
severity, and progression of multi-systemic symptoms that can vary dramatically between individuals and even
across members of the same family. DM1 is caused by a CTG repeat expansion in the DMPK gene that are
transcribed into RNA with long CUG repeats that bind to and sequester important regulators of pre-mRNA
splicing. Consequently, a molecular hallmark of DM1 is the mis-splicing of a subset of genes that contribute to
disease phenotypes. The CTG repeat expansions are also highly unstable and continues to expand over time
at different rates within an individual with DM1, resulting in a high degree of somatic mosaicism that we
hypothesize contributes to the symptomatic variability in this progressive disease. Furthermore, up to 80% of
individuals with DM1 have cardiac defects that result in life-threatening arrhythmias and sudden cardiac death,
composing up to 30% of all mortality in this disease. However, most alternative splicing studies on the cardiac
features of DM1 have only been done on mouse models. To establish whether mis-splicing events discovered
in mouse models are conserved in humans and with similar functional consequences, more studies are needed
on clinically relevant samples.
 This overall goal of this project is to leverage big transcriptomic data with single-cell resolution along
with hypothesis-driven research using molecular and genomic tools to investigate disease mechanisms and
therapeutic methods for DM1. Single-cell RNA sequencing (scRNA-seq) will be done on human induced
pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from DM1 patients and from unaffected
individuals. The data generated will then be analyzed using recent bioinformatical methods to generate a
transcriptome-wide study of alternative splicing in iPSC-CMs and reveal the cellular mosaicism and cardiac
pathogenesis in DM1. Additionally, antisense oligonucleotides will be designed to correct mis-splicing events
and determine its contribution to disease phenotypes in DM1 iPSC-CMs. The underlying hypothesis is that
novel pathogenic mis-splicing events can be identified from scRNA-seq of DM1 iPSC-CMs that have previously
been masked in bulk RNA sequencing and modulating these mis-splicing events can help rescue cardiac
phenotypes. The outcome of this project will: 1) determine the single-cell alternative splicing profile of iPSC-
CMs, 2) elucidate the connection between somatic mosaicism and the phenotypic variability in DM1, 3) identify
pathogenic mis-splicing events in DM1, and 4) reveal potential approaches to correct deleterious mis-splicing.

## Key facts

- **NIH application ID:** 10068568
- **Project number:** 1F32HL154597-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Paul Pang
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2020-08-12 → 2022-08-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068568

## Citation

> US National Institutes of Health, RePORTER application 10068568, Single-cell splicing analysis of the heart in myotonic dystrophy (1F32HL154597-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068568. Licensed CC0.

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