Myotonic dystrophy (DM) is a genetic disorder most known for causing muscle weakness and myotonia, but it affects many body systems including the gastrointestinal (GI) tract. DM patients often experience altered GI tract motility and small intestinal bacterial overgrowth, but the underlying mechanisms are poorly understood. DM is caused by expansion of a CUG repeat RNA that is encoded by the 3’ UTR of the DMPK gene. The MBNL family of RNA-binding proteins are sequestered by the CUG repeats, preventing them from regulating alternative splicing.
We generated several zebrafish DM models by creating CRISPR mutants of each MBNL gene and by inserting transgenes that overexpress CUG repeats globally and in specific tissues. Preliminary studies indicate that DM model fish exhibit some of the same alternative splicing changes that are seen in humans.
We will use these models to study the digestive phenotypes of DM and how microbiota contribute to them. Specifically, we will compare gut motility between WT and DM model fish, and will investigate the specific cell types that contribute to any phenotypes. We will ask how bacteria are altered in DM models, and whether this leads to intestinal inflammation. In addition, we will use germ-free fish to ask whether altered microbiota are necessary or sufficient to cause DM-related digestive phenotypes. Finally, we will investigate how alternative splicing changes contribute to digestive phenotypes.
Overall, these studies will provide important insight into the mechanisms behind the digestive symptoms of DM and the role, if any, that microbes play in them.