Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, with an incidence of about 1 in 8,000 adults. The most common form of the disease, DM1, is caused by an expanded CTG repeat in the 3'UTR of the DMPK gene, and CUG repeat RNAs from this gene fold into hairpins that accumulate in nuclear foci, resulting in effective depletion of the alternative splicing factor Muscleblind (MBNL1) and hyperactivation of the splicing factor CUG Binding Protein 1 (CUGBP1). Misregulation of splicing by these factors is central in the disease. Thus, characterization of the spectrum of changes in the transcriptomes of DM patients is central to understanding disease pathogenesis. This project seeks to understand the molecular basis of DM and to identify genes and mRNA isoforms suitable for therapeutic intervention using an approach based on next-generation sequencing of mRNAs. The project has the following specific aims: 1) To generate a comprehensive catalog of genes, exons and mRNA isoforms whose expression is altered in DM, and to assess the variability of these changes between individuals. 2) To characterize gene and mRNA isoform expression changes in mouse models of DM. 3) To associate gene and isoform changes with clinical and pathological features in DM. Achieving these aims will lay the foundation for a deeper understanding of DM and will generate leads for future molecular genetics and screening studies and is likely to identify candidate therapeutic targets. PUBLIC HEALTH RELEVANCE: This research project will comprehensively determine the changes in RNA and protein molecules that occur in the muscles of patients affected by myotonic dystrophy, which is the most common adult onset form of muscular dystrophy, affecting 1 in 8,000 adults. Knowledge of these molecular changes will help to identify which molecules and genes underlie specific symptoms of the disease and will aid in identifying targets for therapy.
NIH ExPorter
NIH ExPorter