Instability of repetitive DNA sequences causes several diseases, including the progressive multisystemic disorder myotonic dystrophy type 1 (DM1). DM1 symptoms range in severity from muscle weakness and wasting to respiratory insufficiency and premature death, and worsen with age. Thus far, no animal models have successfully recapitulated the multisystemic nature of DM1, nor recreated the genetic basis of DM1. Our goal was to generate and assess mouse models with expanded CTG sequences in the gene Dmpk—as in humans with DM1—in order to investigate the disease’s pathogenesis. Dmpk CTGexp knockin mouse models have been generated, including lines with 170 or 480 uninterrupted CTG repeats. We demonstrate that cells involved in skeletal muscle formation and cerebrospinal fluid (CSF) secretion are especially sensitive to perturbation by Dmpk CTGexp and RNA mis-splicing, suggesting that a- or pre- symptomatic DM1 patients may display signs of dysregulated muscle regeneration and impaired CSF homeostasis. Many of the top splicing changes were previously characterized in DM1 patients’ samples. Our results support Dmpk CTGexp knockin as a model for DM1, and work is underway to create longer repeat expansion knockins to better study DM1 pathogenesis.

[1] Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, [2] Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida 32610, USA