The mechanisms by which CUG repeats cause myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is caused by CUG expansion (CUG exp) at the 3' UTR of the dystrophia myotonica-protein kinase gene (DMPK), leading to charateristic myotonia, progressive muscle wasting and insulin resistance. To test whether MBNL1 sequestration due to expanded CUG repeats is sufficient to explain all defects in DM1, we compared two DM1 mouse models, one expressing a CUGexp transgene, and another homozygous for a defective MBNL1 gene.;At the splicing level, a loss of MBNL1 accounts for 80∼90% of aberrant splicing events in skeletal muscle tissues, indicating an essential role for MBNL1 in the splicing regulation in DM1. More than 50% of the splicing perturbations observed in skeletal muscle tissues also occur in MBNL1 defective mice heart, suggesting a common pathogenic mechanism caused by loss of MBNL1 in those tissues in DM1. As the primary splicing factor in DM1, MBNL 1 has dual functional roles as a repressor and an activator via a yGCy-containing binding motif in the intron regulatory region.;At the transcriptional level, a loss of MBNL1 mRNA is responsible for 70% of the gene expression changes associated with myofiber contraction and glucose metabolism, whereas the other 30% is caused by an MBNL1-independent mechanism that is particularly involved in the extracellular matrix (ECM) that links to muscular dystrophy. Interestingly, we found that depletion of MBNL2 in the C2C12 cell line is associated with differential expression of ECM. Furthermore, compared to MBNL1, MBNL2 dominantly contributes to the observed expression changes in C2C12 cells via siRNA-mediated down-regulation, indicating a functional specialization among the muscleblind proteins.;Our study demonstrates two pathogeneses caused by CTGexp in DM1, whereby a loss of MBNL1 contributes to a splicing perturbation, and another MBNL1-independent mechanism attributes to ECM gene expression changes, possibly mediated by MBNL 2.