Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the DMPK gene. The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2), have provided strong support that RNA gain of function effects play an important role in DM manifestations in skeletal muscle. Although the CNS deficits are one of the most clinically significant aspects of DM, the molecular mechanisms underlying these changes have been unclear. Progress during the current funding period extends our understanding of the CNS features of the disease and molecular mechanisms of microsatellite expansion mutations. Project #3 (PI: Day) has established that DM results in a striking diffuse abnormality of white matter integrity that parallels the cognitive deficits in children, and executive function deficits in adults. Project #2 (PI: Swanson) has extended our understanding of the role of RNA gain of function effects by demonstrating that another member of the MBNL gene family, MBNL2, is a critical regulator of alternative splicing during postnatal brain development. Project #1 (PI: Ranum) has made the unexpected discovery that microsatellite expansion mutations can express homopolymeric expansion proteins without the canonical AUG-initiation codon and that novel proteins accumulate in DM patient tissue. These results suggest novel expansion proteins contribute to DM. The focus of this proposal will be to better understand the clinical consequences of the DM1 and DM2 mutations and to relate specific clinical phenotypes to underlying molecular deficits. To accomplish these goals we propose 3 Projects and 2 Cores: Project 1: Repeat-Associated Non-ATG Translation in DM1 and DM2 Project 2: Mechanisms of RNA-Mediated CNS Pathogenesis in Myotonic Dystrophy Project 3: Clinical and Genetic Characterization of Myotonic Dystrophy Core A: Neuropathology/Functional Imaging Core Core B: Administrative Core.

Public Health Relevance

The goals of this Program are to understand how myotonic dystrophy mutations cause specific brain abnormalities that affect cognition and sleep. We will use an interdisciplinary approach to understand these problems and identify the underlying molecules that contribute to disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Nuckolls, Glen H
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University of Florida
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Pattamatta, Amrutha; Cleary, John D; Ranum, Laura P W (2018) All in the Family: Repeats and ALS/FTD. Trends Neurosci 41:247-250
Sznajder, ?ukasz J; Thomas, James D; Carrell, Ellie M et al. (2018) Intron retention induced by microsatellite expansions as a disease biomarker. Proc Natl Acad Sci U S A 115:4234-4239
Chen, Gang; Carter, Russell E; Cleary, John D et al. (2018) Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy. Neurobiol Dis 112:35-48
Cleary, John Douglas; Pattamatta, Amrutha; Ranum, Laura P W (2018) Repeat-associated non-ATG (RAN) translation. J Biol Chem 293:16127-16141
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Nakamori, Masayuki; Hamanaka, Kohei; Thomas, James D et al. (2017) Aberrant Myokine Signaling in Congenital Myotonic Dystrophy. Cell Rep 21:1240-1252
Zu, Tao; Cleary, John D; Liu, Yuanjing et al. (2017) RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron 95:1292-1305.e5
Thomas, James D; Sznajder, ?ukasz J; Bardhi, Olgert et al. (2017) Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy. Genes Dev 31:1122-1133
Cleary, John Douglas; Ranum, Laura Pw (2017) New developments in RAN translation: insights from multiple diseases. Curr Opin Genet Dev 44:125-134
Moloney, Christina; Rayaprolu, Sruti; Howard, John et al. (2016) Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype. Acta Neuropathol Commun 4:122

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