Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DM protein kinase (DMPK) gene. Transcripts from the mutant allele contain an expanded CUG repeat, and are retained in the nucleus. This results in reduction of the kinase protein and toxicity of the mutant RNA. One mechanism for RNA toxicity is that splicing factors in the Muscleblind-like (MBNL) family are sequestered by the CUG-expanded RNA. This leads to abnormal regulation of alternative splicing and defects of miRNA biogenesis. It appears that many aspects of DM1 result from RNA toxicity (myotonia, insulin resistance) but DMPK reduction may contribute to the cardiac phenotypes. Deletion of Dmpk in mice produces cardiac conduction defects that are similar to those observed human DM1. This suggests that cardiac phenotypes of DM1 may result from combined effects of DMPK deficiency and RNA toxicity, but this possibility has not been rigorously tested. Studies in transgenic mice indicate that features of DM1 in skeletal muscle are reversible by targeting the mutant RNA with antisense oligonucleotides (ASOs). However, it is unclear whether this approach will be effective in the heart. In skeletal muscle, the nuclear-retained mutant transcripts are sensitized to ASOs, providing a mechanism for preferential knockdown of RNA from the mutant allele. Whether ASOs provide a method for cardiac correction without exacerbating DMPK deficiency is unknown. Here we propose to study the impact of DMPK deficiency on cardiac function, in the presence and absence of CUG-expanded RNA, and the feasibility of using ASOs to target CUG-expanded transcripts in the heart.
Aim 1 will characterize the effects of constitutive Dmpk deficiency on cardiac conduction and contractile function in mice. Acquired (ASO-mediated) Dmpk deficiency will also be examined.
Aim 2 will use transgenic mice to examine the effects of CUG-expanded RNA on alternative splicing, miR-1 biogenesis, and cardiac function in vivo.
Aim 3 will use mouse models to test for synergistic effects of RNA toxicity and Dmpk deficiency in the heart.
Aim 4 will use mice with RNA toxicity and Dmpk deficiency - the condition that approximates the molecular lesion in human DM1 heart - to assess therapeutic effects of ASOs on cardiac function in vivo.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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University of Rochester
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