Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects

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Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslated portion of the dystrophica myotonica protein kinase gene. The identification and characterization of RNAbinding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain of function mechanism in which CUG and CCUG expansion transcripts lead to the dysregulation of key RNAbinding proteins, including muscleblind (MbnH) and CUG-binding protein (CUG-BP), which in turn lead to the downstream dysregulation of specific set of genes that cause the multisystemic features common to both diseases. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecular mechanisms underlying these changes are unclear. Only DM1 causes developmental defects, including mental retardation, but both forms of DM result in degenerative CNS effects that have not yet been well characterized. The focus of this proposal is to characterize the CNS effects of the DM1 and DM2 mutations in patients through imaging studies and neuropsychological testing and to relate these changes to the underlying molecular deficits through the generation and characterization of mouse models. To accomplish these goals the following Projects and Cores are proposed as part of our overall Program entitled: Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects. Project 1: Temporal/spatial RNA expression effects in DM1 and DM2 Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic Dystrophy Project 3: Structural and Functional CNS Changes in Children with Myotonic Dystrophy Type 1 Core A: Neuropathology and Optical Imaging Core Core B: Administrative Core