Abstract for presentation at 11th International Congress of Human Genetics

Myotonic muscular dystrophy (DM), an autosomal dominant disease, is the most common inherited neuromuscular disorder in adults with a reported global incidence of approximately 1:8000. DM is a multisystemic disorder affecting all three muscle lineages and other systems. Amongst a variety of features including catarcts, smooth muscle dysfunction, neurologic symptoms and endocrine abnormalities, patients have myotonia (impaired relaxation of muscle after voluntary contraction)and cardiac conduction abnormalities as prominent aspects of the disease. The DM1 mutation is an expansion of a (CTG)n tract in the 3’ untranslated region (3’UTR) of the DM protein kinase (DMPK) gene and thus does not affect protein structure. Consequently, the pathogenic mechanism has been one of the major enigmas of human genetics but an emerging hypothesis is that DM may be the first example of a disease caused by RNA toxicity. To address this, we have generated inducible transgenic mice expressing the DMPK 3’UTR as part of a RNA transcript encoding green fluorescent protein (GFP). Upon induction of the transgene with doxycycline, we observed the toxic effects of the DMPK 3’UTR mRNA on muscle resulting in myotonia, and for the first time on cardiac muscle resulting in various cardiac conduction abnormalities. Furthermore, the toxicity was reversible in both skeletal and cardiac muscles by silencing expression of the transgene. These results represent a unique reversible mouse model of cardiac conduction abnormality and establish proof of principle for a therapeutic strategy for treatment of DM through ablation or silencing of the toxic RNA molecules.