The RNA‐binding protein Staufen interacts with DMPK transcripts in skeletal muscle: New insights into the mechanisms underlying myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder that results in several characteristic symptoms including myotonia, muscle weakness, facial changes, cataracts, reduced cognitive abilities, heart block and endocrine abnormalities. The disease is caused by a CUG expansion in the 3′UTR of the myotonic dystrophy protein kinase (DMPK) mRNA. It is believed that mutant DMPK transcripts cause a toxic RNA gain of function as they sequester through their expansion, RNA‐binding proteins and transcription factors destined to normally regulate other target mRNAs and/or genes. Here, we initiated a series of experiments aimed at determining whether Staufen, known for its key role in mRNA transport, participates in the complex DM1 pathology. In muscle, Staufen and DMPK accumulate at the neuromuscular junction. Using immunoprecipitation analysis, we demonstrate that Staufen binds to DMPK mRNA in skeletal muscle cells. Interestingly, levels of Staufen are significantly increased in muscles from a DM1 mouse model engineered to express a pathogenic transgene containing 250 CTG repeats. Finally, we observed that overexpression of Staufen in C2C12 muscle cells inhibits their differentiation. We therefore propose that Staufen, as an RNA‐binding protein that interacts with DMPK transcripts, contributes to the basic mechanisms underlying the complex phenotype associated with DM1. Funded by CIHR.