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 RNA-binding 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 RNA-binding 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

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Porter, John D
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University of Florida
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Pletnikova, Olga; Sloane, Kelly L; Renton, Alan E et al. (2014) Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 35:2419.e17-21
Mohan, Apoorva; Goodwin, Marianne; Swanson, Maurice S (2014) RNA-protein interactions in unstable microsatellite diseases. Brain Res 1584:3-14
Batra, Ranjan; Charizanis, Konstantinos; Manchanda, Mini et al. (2014) Loss of MBNL leads to disruption of developmentally regulated alternative polyadenylation in RNA-mediated disease. Mol Cell 56:311-22
Cleary, John Douglas; Ranum, Laura P W (2014) Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Curr Opin Genet Dev 26:6-15
Wozniak, Jeffrey R; Mueller, Bryon A; Lim, Kelvin O et al. (2014) Tractography reveals diffuse white matter abnormalities in Myotonic Dystrophy Type 1. J Neurol Sci 341:73-8
Goodwin, Marianne; Swanson, Maurice S (2014) RNA-binding protein misregulation in microsatellite expansion disorders. Adv Exp Med Biol 825:353-88
Hernandez-Hernandez, Oscar; Guiraud-Dogan, Celine; Sicot, Geraldine et al. (2013) Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour. Brain 136:957-70
Cramer, Samuel W; Gao, Wangcai; Chen, Gang et al. (2013) Reevaluation of the beam and radial hypotheses of parallel fiber action in the cerebellar cortex. J Neurosci 33:11412-24
Zhang, Chaolin; Lee, Kuang-Yung; Swanson, Maurice S et al. (2013) Prediction of clustered RNA-binding protein motif sites in the mammalian genome. Nucleic Acids Res 41:6793-807
Cleary, John D; Ranum, Laura P W (2013) Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet 22:R45-51

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