Figure 1.

Molecular mechanisms underlying DM1 pathology identified in Drosophila. DM1 is caused by microsatellite repeat expansions (n > 50 CTG repeats) in 3’UTR region of DMPK gene. Mutant DMPK transcripts are retained in the nucleus and form nuclear foci that sequester MBNL1/Mbl and stabilize CELF1/Bru3 proteins leading to missplicing. Bru3 stabilization also induces down-regulation of sarcomeric proteins associated with impaired motility and muscle morphology defects [59], whereas loss of MBNL1/Mbl blocks pre miR-1 processing [53] leading to up regulation of its target genes such as GJA1 and CACNA1C suggested as associated with conduction defects and arrhythmias/sudden death, respectively [45]. Both Bru3 stabilization and Mbl sequestration induce up regulation of Stj and down regulation of Rgk2 expression associated with conduction defects [47]. CTG repeats could be transcribed in both directions leading to CAGn–CUGn double stranded complexes and formation of siRNA duplex that interact with RISC complex to target the expression of genes containing CAG repeats, such as Ataxin-2 (ATXN2) and TATA binding protein (TBP) [38]. Long CTG repeats induce down regulation of genes in a splicing independent manner including genes involved in carbohydrate metabolism and oxidation-reduction processes [52].