GSE125638
Distinct Pathological Signatures in Human Cellular Models of Myotonic Dystrophy Subtypes
Myotonic dystrophy (DM) is the most common autosomal dominant muscular dystrophy and encompasses both skeletal muscle and cardiac complications.  Myotonic dystrophy is nucleotide repeat expansion disorder in which type 1 (DM1) is due to a trinucleotide repeat expansion on chromosome 19 and type 2 (DM2) arises from a tetranucleotide repeat expansion on chromosome 3.  Developing representative models of myotonic dystrophy in animals has been challenging due to instability of nucleotide repeat expansions, especially for DM2 which is characterized by nucleotide repeat expansions often greater than 5000 copies.  To investigate mechanisms of human DM, we generated cellular models of DM1 and DM2.  We used regulated MyoD expression to reprogram urine-derived cells into myotubes.  In this cell model, we found impaired dystrophin expression, MBNL foci, and aberrant splicing in DM1 but not in DM2 cells.  We generated induced pluripotent stem cells (iPSC) from healthy controls, DM1 and DM2 subjects and differentiated these into cardiomyocytes.  DM1 and DM2 cells displayed an increase in RNA foci concomitant with cellular differentiation.  IPSC-derived cardiomyocytes from DM1 but not DM2 had aberrant splicing and MBNL sequestration.  High resolution imaging revealed tight association between MBNL clusters and RNA FISH foci in DM1.  Ca2+ transients differed between DM1 and DM2 IPSC-derived cardiomyocytes and from healthy control cells.  RNA-sequencing from DM1 and DM2 iPSC-derived cardiomyocytes both altered gene expression as well as distinct splicing patterns as differential between DM1 and DM2.  Together these data support that DM1 and DM2, despite some shared clinical and molecular features, have distinct pathological signatures. Overall design: 2 Control, 2 Myotonic Dystrophy Type 1, and 2 Myotonic Dystrophy type 2 IPSC-cardiomyocytes were analyzed.