Go to The Journal of Clinical Investigation
Insight white on transparent.20160208
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All...
  • Videos
  • Collections
    • Recently published
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

Insight white on transparent small

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Transfers
  • Current issue
  • Past issues
  • By specialty
  • Contact
  • Recently published
  • Technical Advances
  • Clinical Medicine
  • Editorials
  • Top read articles
Top
  • View PDF Adobe pdf file icon
  • Download citation information
  • Send a letter
  • License information
  • Standard abbreviations
  • Article usage
  • Citations to this article
  • Share this article
  • Need Help? E-mail the JCI Insight
  • Top
  • Abstract
  • Supplemental material
  • Version history
Advertisement

ResearchIn-Press PreviewCardiologyStem cells Free access | 10.1172/jci.insight.122686

Distinct pathological signatures in human cellular models of myotonic dystrophy subtypes

Ellis Y. Kim, David Y. Barefield, Andy H. Vo, Anthony M. Gacita, Emma J. Schuster, Eugene J. Wyatt, Janel L. Davis, Biqin Dong, Cheng Sun, Patrick Page, Lisa Dellefave-Castillo, Alexis Demonbreun, Hao F. Zhang, and Elizabeth M. McNally

Find articles by Kim, E. in: JCI | PubMed | Google Scholar

Find articles by Barefield, D. in: JCI | PubMed | Google Scholar | Orcid 24x24

Find articles by Vo, A. in: JCI | PubMed | Google Scholar

Find articles by Gacita, A. in: JCI | PubMed | Google Scholar

Find articles by Schuster, E. in: JCI | PubMed | Google Scholar

Find articles by Wyatt, E. in: JCI | PubMed | Google Scholar

Find articles by Davis, J. in: JCI | PubMed | Google Scholar

Find articles by Dong, B. in: JCI | PubMed | Google Scholar | Orcid 24x24

Find articles by Sun, C. in: JCI | PubMed | Google Scholar | Orcid 24x24

Find articles by Page, P. in: JCI | PubMed | Google Scholar

Find articles by Dellefave-Castillo, L. in: JCI | PubMed | Google Scholar

Find articles by Demonbreun, A. in: JCI | PubMed | Google Scholar

Find articles by Zhang, H. in: JCI | PubMed | Google Scholar | Orcid 24x24

Find articles by McNally, E. in: JCI | PubMed | Google Scholar

First published February 7, 2019 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.122686.
Copyright © 2019, American Society for Clinical Investigation

First published February 7, 2019 - Version history
Abstract

Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications. Myotonic dystrophy is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3. Developing representative models of myotonic dystrophy in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2 which is characterized by nucleotide repeat expansions often greater than 5000 copies. To investigate mechanisms of human DM, we generated cellular models of DM1 and DM2. We used regulated MyoD expression to reprogram urine-derived cells into myotubes. In this myogenic cell model, we found impaired dystrophin expression, MBNL foci, and aberrant splicing in DM1 but not in DM2 cells. We generated induced pluripotent stem cells (iPSC) from healthy controls, DM1 and DM2 subjects and differentiated these into cardiomyocytes. DM1 and DM2 cells displayed an increase in RNA foci concomitant with cellular differentiation. IPSC-derived cardiomyocytes from DM1 but not DM2 had aberrant splicing of known target genes and MBNL sequestration. High resolution imaging revealed tight association between MBNL clusters and RNA FISH foci in DM1. Ca2+ transients differed between DM1 and DM2 IPSC-derived cardiomyocytes and each differed from healthy control cells. RNA-sequencing from DM1 and DM2 iPSC-derived cardiomyocytes revealed distinct misregulation of gene expression as well as differential aberrant splicing patterns. Together these data support that DM1 and DM2, despite some shared clinical and molecular features, have distinct pathological signatures.

Graphical Abstract
graphical abstract
Supplemental material

View Supplementary Information

Version history
  • Version 1 (February 7, 2019): In-Press Preview

Article tools

  • View PDF Adobe pdf file icon
  • Download citation information
  • Send a letter
  • License information
  • Standard abbreviations
  • Article usage
  • Citations to this article
  • Share this article
  • Need Help? E-mail the JCI Insight

Go to:

  • Top
  • Abstract
  • Supplemental material
  • Version history
Advertisement
Advertisement
Follow JCI Insight: Facebook logo white Twitter logo v2 Rss icon
Copyright © 2019 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts