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

Genes Dev. 2019 Dec 1;33(23-24):1635-1640. doi: 10.1101/gad.328963.119. Epub 2019 Oct 17.


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.

Keywords: MBNL; RNA splicing; myotonic dystrophy; neuromuscular disease; short tandem repeat.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Alternative Splicing / genetics*
  • Animals
  • Choroid Plexus / physiopathology
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental
  • Gene Knock-In Techniques
  • Mice
  • Microsatellite Repeats / genetics*
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / physiopathology*
  • Mutation
  • Myotonic Dystrophy / genetics*
  • Myotonic Dystrophy / physiopathology*
  • Myotonin-Protein Kinase / genetics
  • Myotonin-Protein Kinase / metabolism
  • RNA Splicing / genetics*
  • RNA-Binding Proteins / genetics


  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • Mbnl1 protein, mouse
  • RNA-Binding Proteins
  • Myotonin-Protein Kinase