Myotonic dystrophy (DM) is the second most common cause of muscular dystrophy and the most common cause of adult onset muscular dystrophy. The disease is dominantly inherited, multisystemic, and phenotypically variable. The mutations that cause DM are expanded tri- (CTG) and tetra- (CCTG) nucleotide repeats located within untranslated regions of transcribed genes. Pathogenesis involves a novel mechanism in which RNA transcribed from the expanded allele exerts a toxic gain-of-function. Recent evidence indicates that an RNA gain-of-function is an important component of other microsatellite expansion disorders such as Spinocerebellar Ataxia 8 (SCA8), Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), and Huntington Disease-Like 2 (HDL2). One mechanism by which the expanded repeat RNA exerts a gain-of-function in DM is by sequestration of RNA binding proteins such as the muscleblind-like (MBNL) family, resulting in a loss-of-function. We have identified a second mechanism in which expanded repeat RNA activates protein kinase C (PKC) and induces PKC-dependent phosphorylation of a second RNA binding protein, CUG-binding protein 1 (CUGBP1), resulting in its stabilization and up-regulation. MBNL and CUGBP1 normally regulate pre-mRNA alternative splicing during development and the disruption of their functions in DM results in the splicing defects that have previously been linked with causation of disease symptoms. The finding that RNA from a microsatellite expansion induces a signaling event has broad implications to the mechanism of pathogenesis. The goals of this proposal are to determine the mechanism by which expanded repeat RNA activates a signaling event, investigate the immediate effects on CUGBP1 function, determine the broader consequences, and relate these effects of the expanded repeats to mechanisms of inhibited skeletal muscle differentiation in cell culture and wasting of skeletal muscle tissue. The latter aspect of the investigation will be performed using a newly developed DM1 mouse model that reproduces features of the disease including severe skeletal muscle wasting. At the completion of these studies, we will have established the contributions to disease pathogenesis of a newly discovered signaling event stimulated by microsatellite-derived RNA. These results will provide new therapeutic targets to prevent or circumvent the molecular events leading to muscle wasting.

Public Health Relevance

Myotonic dystrophy is the second most common cause of muscular dystrophy in the United States. It is caused by an unusual kind of mutation and a previously unknown mechanism. We will use cell culture and mouse models of the to determine the mechanism of disease. This information will be used to develop therapeutic approaches to reverse or circumvent disease processes.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-L (07))
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Nuckolls, Glen H
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Baylor College of Medicine
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