? Myotonic dystrophy type 1 (DM1) is one of the most variable diseases known to medicine. Research on this disorder has led to the recognition of RNA toxicity, a new paradigm for muscle disease. The mutation in DMl, an expanded CTG repeat in the 3'untranslated region of DMPK, is genetically unstable. Increases of CTG expansion size in subsequent generations are associated with greater severity of disease. Deleterious effects of the expansion are mediated by mutant RNA, which contains an expanded CUG repeat. Splicing factors that bind to CUG expansions are sequestered, which leads to abnormal regulation of alternative splicing. Recognition of this mechanism has fostered the development of targeted therapies for DM1. As new treatments advance into clinical trials, there is a compelling need for clinical endpoints that are reliable and sensitive indicators of the therapeutic response. The process of testing new agents will be greatly assisted by the availability of biomarkers that accurately reflect drug activity in muscle tissue. Furthermore, it is increasingly important to understand the biological basis for DM1 variability, because this may confound clinical outcomes or impact the individual response to targeted therapies. We have found that some individuals with very large CTG expansions in muscle tissue do not exhibit severe muscle weakness, suggesting that genetic factors other than expansion size may influence DM1 severity.
Aim 1 of this project will quantify longitudinal changes of DM1 across a wide spectrum of patients, and identify endpoints that are sensitive for detecting disease progression.
Aim 2 will determine whether it is feasible to monitor splicing defects in muscle tissue in multicenter studies. We also plan to qualify a group of splicing events as biomarkers of DM1 severity.
Aim 3 will standardize myotonia assessment as a physiological indicator of RNA toxicity.
Aim 4 will test the hypothesis that CTG expansion length is not a unitary explanation for DM1 severity. Genetic modifiers of DM1 will be sought, first by examining a candidate locus and then by testing for associations across the entire genome. Overall, this project will supply critical information that is needed to move forward with therapeutic development in DM1.

Public Health Relevance

;This project will supply critical information that is needed to move forward with development of new treatments for myotonic dystrophy type 1. This project seeks to identify the best ways to evaluate and interact with patients to demonstrate the effectiveness of promising new therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZNS1-SRB-S)
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University of Rochester
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