Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslatedportion of the dystrophica myotonica protein kinase gene. The identification and characterization of RNAbindingproteins that interact with expanded CUG repeats and the discovery that a similar transcribed butuntranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have uncovered a newtype of mechanism in which microsatellite expansion mutations cause disease through an RNA gain offunction mechanism in which CUG and CCUG expansion transcripts lead to the dysregulation of key RNAbindingproteins, including muscleblind (MbnH) and CUG-binding protein (CUG-BP), which in turn lead to thedownstream dysregulation of specific set of genes that cause the multisystemic features common to bothdiseases. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecularmechanisms underlying these changes are unclear. Only DM1 causes developmental defects, includingmental retardation, but both forms of DM result in degenerative CNS effects that have not yet been wellcharacterized. The focus of this proposal is to characterize the CNS effects of the DM1 and DM2 mutationsin patients through imaging studies and neuropsychological testing and to relate these changes to theunderlying molecular deficits through the generation and characterization of mouse models. To accomplishthese goals the following Projects and Cores are proposed as part of our overall Program entitled: MyotonicDystrophy: Molecular Pathophysiology and CNS Effects.Project 1: Temporal/spatial RNA expression effects in DM1 and DM2Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic DystrophyProject 3: Structural and Functional CNS Changes in Children with Myotonic Dystrophy Type 1Core A: Neuropathology and Optical Imaging CoreCore B: Administrative Core
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