Project One: DM2 Pathomechanisms and Therapeutic Development

Project Co-Leaders: Laura P. W. Ranum Ph.D. and Maurice S. Swanson Ph.D., University of Florida

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are dominantly inherited muscular dystrophies caused by short tandem repeat expansions in the noncoding regions of two different genes. While DM1 results from CTG trinucleotide expansions in the DMPK 3’ untranslated region, DM2 is caused by structurally similar CCTG tetranucleotide expansions in intron 1 of the CNBP gene. DM1 and DM2 share underlying pathomechanisms since transcription of mutant DMPK and CNBP genes produces expanded CUG and CCUG RNAs, respectively, that are pathogenic because they alter the activities of the MBNL family of developmentally regulated RNA processing factors while also serving as templates for repeat-associated non-AUG (RAN) translation. Importantly, DM2 represents an emerging and prevalent class of STR expansion diseases caused by intronic mutations. Therapeutic development for DM1 has been prioritized since it is the most common form of adult-onset muscular dystrophy, and several mouse models such as HSA^LR have been used extensively to evaluate potential therapies in vivo. In contrast, DM2 mouse models that replicate the DM2 clinical presentation have not been reported. To address this deficiency, the aims of this project are to develop novel DM2 mouse models designed to improve our pathomechanistic understanding of DM2 and then use these models as tools to accelerate therapeutic testing in vivo. The aims are: 1) generate and characterize DM2 BAC transgenic models and test if these mice reproduce key pathophysiological hallmarks of DM2 disease; 2) evaluate a CCTG overexpression transgenic mouse model to define DM2 biochemical and pathophysiological mechanisms and compare these outcomes to the HSA^LR DM1 model; 3) use these DM2 mouse models to test potential therapies for DM2 that either selectively target mutant CNBP RNAs or CNBP transcription.