Molecular Mechanism of Myotonic Dystrophy: RNA Gain-of-Function
Myotonic dystrophy (DM1 & DM2) is a complex neuromuscular disorder with autosomal dominant pattern of inheritance. Myotonic dystrophy associated with DNA expansion mutations in two different genes. In DM1 a CTG repeat in the 3'-untranslated region of DMPK is expanded, whereas in DM2 an intronic CCTG expansion occurs in the gene ZNF9. CUG and CCUG expanded repeat transcripts from both genes produced foci in the nuclei of DM1 and DM2 cells but not in normal cells. Proteins encoded by the three different muscleblind genes, MBNL1, MBNL2 (MBLL) and MBNL3 (MBXL) sequestered by foci of expanded repeat transcripts. Sequestered mucleblind proteins on CUG or CCUG repeat-containing RNA results in dilution of these proteins from their normal function. Splicing of some important transcripts is altered in DM patients as a downstream effects of muscleblind proteins dilution. The muscleblind genes are also show extensive alternative splicing. Here we identified a new splicing form of MBNL2 which might be important in pathological features of myotonic dystrophy.