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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
2P01NS058901-07A1
Application #
8609099
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Porter, John D
Project Start
2007-04-01
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$1,261,372
Indirect Cost
$291,158
Name
University of Florida
Department
Genetics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Freyermuth, Fernande; Rau, Frédérique; Kokunai, Yosuke et al. (2016) Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nat Commun 7:11067
Scotti, Marina M; Swanson, Maurice S (2016) RNA mis-splicing in disease. Nat Rev Genet 17:19-32
Goodwin, Marianne; Mohan, Apoorva; Batra, Ranjan et al. (2015) MBNL Sequestration by Toxic RNAs and RNA Misprocessing in the Myotonic Dystrophy Brain. Cell Rep 12:1159-68
Hewitt, Angela L; Popa, Laurentiu S; Ebner, Timothy J (2015) Changes in Purkinje cell simple spike encoding of reach kinematics during adaption to a mechanical perturbation. J Neurosci 35:1106-24
Coram, Ryan J; Stillwagon, Samantha J; Guggilam, Anuradha et al. (2015) Muscleblind-like 1 is required for normal heart valve development in vivo. BMC Dev Biol 15:36
Xia, Guangbin; Gao, Yuanzheng; Jin, Shouguang et al. (2015) Genome modification leads to phenotype reversal in human myotonic dystrophy type 1 induced pluripotent stem cell-derived neural stem cells. Stem Cells 33:1829-38
Batra, Ranjan; Manchanda, Mini; Swanson, Maurice S (2015) Global insights into alternative polyadenylation regulation. RNA Biol 12:597-602
Davis, Jennifer; Salomonis, Nathan; Ghearing, Natasha et al. (2015) MBNL1-mediated regulation of differentiation RNAs promotes myofibroblast transformation and the fibrotic response. Nat Commun 6:10084
Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita et al. (2015) Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nat Commun 6:7205

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