What is DM1?
DM1 is an autosomal dominant rare genetic disease with variable presentation. It is the most common muscular dystrophy in adults and it is highly disabling, causing severe neuromuscular symptoms, including cardiac conduction defects, myotonia, and progressive muscle weakness and wasting (atrophy). Neuropsychological dysfunction is also a common symptom of DM. The genetic cause of DM1 is well known, namely the accumulation of long RNA transcripts due to expanded CTG repeats in the 3'UTR of the DYSTROPHIA MYOTONICA PROTEIN KINASE (DMPK) gene. The complementary RNA CUG repeats aggregate forming ribonuclear foci, a hallmark of the disease. Toxic RNA retains RNA-binding proteins such as MBNL, that are thus depleted from their regular cellular targets. Loss of function of MBNL proteins triggers gene misregulation at the level of transcription, translation, gene silencing, alternative splicing, and polyadenylation of subsets of transcripts. There is ample evidence that loss of MBNL function is critical to the clinical manifestations in DM1. Therefore, boosting expression of MBNL is a potential therapeutic avenue. Indeed, overexpression of MBNL has been shown to rescue disease-associated RNA missplicing and muscle myotonia in a well known DM mouse model, the HSALR model, that expresses 250 CTG repeat units in a human skeletal actin promoter (Kanadia et al. 2006).