Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy

Curtis A. Nutter, Jodi L. Bubenik, Ruan Oliveira, Franjo Ivankovic, Łukasz J. Sznajder, Benjamin M. Kidd, Belinda S. Pinto, Brittney A. Otero, Helmut A. Carter, Eric A. Vitriol, Eric T. Wang, Maurice S. Swanson

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Short tandem repeats (STRs) are prone to expansion mutations that cause multiple hereditary neurological and neuromuscular diseases. To study pathomechanisms using mouse models that recapitulate the tissue specificity and developmental timing of an STR expansion gene, we used rolling circle amplification and CRISPR/Cas9-mediated genome editing to generate Dmpk CTG expansion (CTGexp) knockin models of myotonic dystrophy type 1 (DM1). We demonstrate that skeletal muscle myoblasts and brain choroid plexus epithelial cells are particularly susceptible to Dmpk CTGexp mutations and RNA missplicing. Our results implicate dysregulation of muscle regeneration and cerebrospinal fluid homeostasis as early pathogenic events in DM1.

Original languageEnglish (US)
Pages (from-to)1635-1640
Number of pages6
JournalGenes and Development
Volume33
Issue number23-24
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

Keywords

  • MBNL
  • RNA splicing
  • myotonic dystrophy
  • neuromuscular disease
  • short tandem repeat

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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