RNAseq of myotonic dystrophy type 1 and 2 patient-derived fibroblast cell lines for assessing potential therapeutics

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are common forms of adult onset muscular dystrophy, characterized by autosomal dominant, progressive myopathy with multisystemic involvement. Pathogenesis in both diseases is largely driven by production of toxic repeat RNAs that sequester muscleblind-like (MBNL) RNA binding proteins, causing mis-splicing. Although a number of cell lines for DM1 have been developed and characterized, there are very few available DM2 model systems, limiting therapeutic development for DM2. Here, we characterize several primary DM1 an DM2 patient-derived fibroblast cell lines using optical mapping to measure expanded repeat lengths, FISH to assess RNA foci, and RNA-seq to characterize mis-splicing. Mis-splicing events in several genes were identified to be unique to DM2, but not DM1 fibroblasts. As proof of concept to support their use in therapeutic development, we show that furamidine, and other diamidines, can rescue molecular features in both DM1 and DM2 fibroblasts. Thus, these studies define the molecular and cellular landscape present in these cell lines, filling an important gap that has thus far limited in vitro therapeutic development for DM2.