Skeletal muscle and circulating microRNAs in Myotonic Dystrophy Type 1

Myotonic Dystrophy type 1 (DM1) is a multisystemic disorder that affects skeletal muscles as well as the eye, the heart, the endocrine, and the central nervous systems. The most severe forms are characterized by hypotonia and generalized weakness at birth, often with respiratory insufficiency and early death. DM1 is caused by abnormally expanded stretches of DNA (repeated CTG triplets) occurring in the dystrophia myotonica-protein kinase (DMPK) gene. This mutation causes the accumulation of DMPK gene transcripts (mRNAs) into nuclear clusters called foci and cell dysfunction consequent to RNA toxicity. Toxic RNA leads to aberration of mRNA maturation (splicing) mechanisms, of protein production (translation) and of the function of small regulatory RNAs called microRNAs. Previous work from several groups including ours, has established that the accumulation and the localization of specific microRNAs is altered in DM1 patients. However, the functional implications of these microRNA aberrations for the disease are still largely unknown. The aim of this project is to shed light on the microRNAs that are functionally deregulated in DM1 tissues, potentially allowing the identification of novel therapeutic approaches. Moreover, we have evidence that the microRNA fraction present in the peripheral blood is also specifically deregulated in DM1 patients. The potential of these circulating microRNAs to act as a disease marker for DM1 will be explored. So far, no such biomarkers have been described for DM1 severity/staging evaluation.