Abstract
Myotonic dystrophy type I (DM1) is a multi-system, autosomal dominant disorder caused by expansion of a CTG repeat sequence in the 3′UTR of the DMPK gene. The size of the repeat sequence correlates with age at onset and disease severity, with large repeats leading to congenital forms of DM1 associated with hypotonia and intellectual disability. In models of adult DM1, expanded CUG repeats lead to an RNA toxic gain of function, mediated at least in part by sequestering specific RNA splicing proteins, most notably muscleblind-related (MBNL) proteins. However, the impact of CUG RNA repeat expression on early developmental processes is not well understood. To better understand early developmental processes in DM1, we utilized the zebrafish, Danio rerio, as a model system. Direct injection of (CUG)91 repeat-containing mRNA into single-cell embryos induces toxicity in the nervous system and muscle during early development. These effects manifest as abnormal morphology, behavioral abnormalities and broad transcriptional changes, as shown by cDNA microarray analysis. Co-injection of zebrafish mbnl2 RNA suppresses (CUG)91 RNA toxicity and reverses the associated behavioral and transcriptional abnormalities. Taken together, these findings suggest that early expression of exogenously transcribed CUG repeat RNA can disrupt normal muscle and nervous system development and provides a new model for DM1 research that is amenable to small-molecule therapeutic development.
Highlights
Myotonic dystrophy type I (DM1) is the third most common muscular dystrophy, affecting an estimated one in 10,000 people worldwide (Bird, 2007)
These findings recapitulate some, but not all, of the features observed in adult models of DM1 and demonstrate that the CUG RNA repeat can be toxic despite having limited impact on mRNA splicing
Implications and future directions These data provide evidence that CUG repeat RNA can interfere with early developmental processes in zebrafish, offering insights into the pathogenesis of myotonic dystrophy
Summary
Myotonic dystrophy type I (DM1) is the third most common muscular dystrophy, affecting an estimated one in 10,000 people worldwide (Bird, 2007) It is characterized clinically by effects in multiple organ systems, including muscle, heart and the central nervous system. The CUG repeat expansion as mRNA is able to bind to and sequester specific proteins, most notably the muscleblind-like protein family of splicing factors (MBNL1, MBNL2 and MBNL3). This sequestration is thought to trigger altered splicing and expression of MBNL target mRNAs, which in turn result in the clinical symptoms observed in patients (Mankodi et al, 2000; Kanadia et al, 2003a; Jiang et al, 2004; Kanadia et al, 2006; Lin et al, 2006; Wheeler et al, 2007; Osborne et al, 2009; Du et al, 2010; Wang et al, 2012)
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