Molecular Pathogenesis of Myotonic Dystrophy
Myotonic dystrophy is the most common form of adult onset muscular dystrophy. The congenital form of the disease is associated with mental retardation as well as skeletal muscle and cardiac abnormalities. The mechanism of pathogenesis in myotonic dystrophy is unique in that expansion of CTG or CCTG repeats are the mutation that cause the disease and pathogenesis results from toxicity of the RNA transcripts from expanded alleles containing CUG or CCUG expanded repeats. We have generated and characterized an inducible and tissue specific models for myotonic dystrophy type 1 in which Cre-mediated recombination is used to express mRNA containing human DMPK exon 15 with 960 CUG repeats. The model is such that the disease gene can be induced in different tissues (heart, skeletal muscle, brain) and at different times during development. This provides a huge advance to our studies as this model us to pursue mechanistic investigations that are not feasible otherwise. We have already used this model to identify a previously unrecognized abnormality in tissues from individuals with myotonic dystrophy. The specific goal of this project is to induce expression of disease-causing RNA in the central nervous system to reproduce the congenital form of the disease.
Relevance of the project to IDDRC mission:
Understanding the molecular mechanisms by which the toxic RNA that causes myotonic dystrophy pathogenesis in the CNS is directly relevant to understanding the molecular and cellular basis for mental retardation. Severely reduced cognitive abilities, behavioral abnormalities, and deficits in executive function are well established features of myotonic dystrophy type 1. Having established that our transgenic approach reproduces molecular, cellular, and phenotypic features of DM1 in heart and skeletal muscle, we are now using this approach to reproduce features of the disease in the CNS. We have also established a framework for understanding the molecular basis for the toxic RNA which will now be applied to understanding the mechanisms of learning and behavioral difficulties associated with this disease.