摘要：SummaryMyotonic dystrophy type 1 (DM1) and type 2 (DM2) are common forms of adult onset muscular dystrophy. Pathogenesis in both diseases is largely driven by production of toxic-expanded repeat RNAs that sequester MBNL RNA-binding proteins, causing mis-splicing. Given this shared pathogenesis, we hypothesized that diamidines, small molecules that rescue mis-splicing in DM1 models, could also rescue mis-splicing in DM2 models. While several DM1 cell models exist, few are available for DM2 limiting research and therapeutic development. Here, we characterize DM1 and DM2 patient-derived fibroblasts for use in small molecule screens and therapeutic studies. We identify mis-splicing events unique to DM2 fibroblasts and common events shared with DM1 fibroblasts. We show that diamidines can partially rescue molecular phenotypes in both DM1 and DM2 fibroblasts. This study demonstrates the potential of fibroblasts as models for DM1 and DM2, which will help meet an important need for well-characterized DM2 cell models.Graphical abstractDisplay OmittedHighlights•Myotonic dystrophy 2 fibroblasts show mis-splicing and other disease features•DM1 and DM2 fibroblasts have both common and unique mis-splicing events•Select diamidines rescued mis-splicing in DM1 and DM2 fibroblasts•DM fibroblasts are a viable avenue to model disease and test therapeutic approachesBiochemistry; Small molecule; Molecular physiology
