Large expansion of CTG trinucleotide repeats in the 3? untranslated region of the DMPK gene cause myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy. Toxic CUG repeats-containing RNAs transcribed from the DMPK gene sequester and disable RNA binding proteins that are critical for cell function. At present, there is no therapeutic approach to reduce disease severity or delay disease onset. Several labs are considering approaches aimed at neutralizing the toxic RNA. These could provide short-term effects, unless continuously applied. A strategy that induces the contraction or deletion of the expanded CTG repeats could provide an alternative approach to permanently eliminate the production of the toxic RNA. Expanded CTG repeats have the potential to form hairpins structures in vitro and a mechanism that involves the failure to resolve secondary structures that form sporadically during lagging strand synthesis has been proposed to explain trinucleotide instability. Several lines of evidence suggest that specialized helicases can either facilitate or antagonize expansion of repeat sequences. However, to what extent and under what circumstances specific helicases contribute to repeat stability in vivo is not known. The WRN protein is a member of the RecQ family of helicases that has been shown to resolve secondary structures formed by repetitive G-rich sequences, and in vitro studies from our and other labs have indicated that WRN prevents stalling of the replicative polymerase at these repetitive sequences. To determine whether WRN influences the stability of expanded CTG repeats in vivo, we crossed Wrn knock-out mice with transgenic mice bearing expanded CTG repeats that recapitulate DM1-specific skeletal muscle pathologies. Our preliminary data indicate that Wrn deficiency results in the stochastic loss of the expanded repeats, suggesting that this helicase contributes to the maintenance of long pathogenic CTG repeats in vivo. To gain critical insights on the relationship between WRN and expanded CTG repeats stability and explore the therapeutic potential of WRN inhibition for DM1, we propose to characterize CTG instability in Wrn deficient mice, assess the effects of Wrn deficiency on the skeletal muscle phenotype of DM1 mice, and gain insights on factors that influence CTG repeat instability resulting from WRN deficiency. These studies will reveal the potential value of approaches that target WRN for developing novel therapeutic strategies for DM1.

Public Health Relevance

The studies proposed in this application will elucidate the role that the specialized WRN helicase plays in the metabolism of CTG repeats, which may help to develop strategies for therapeutic interventions in DM1 and possibly other nucleotide repeats expansion disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Therapeutic Approaches to Genetic Diseases Study Section (TAG)
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Nuckolls, Glen H
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University of Southern California
Schools of Medicine
Los Angeles
United States
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