Myotonic dystrophy:: The role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios

The mechanism by which (CTG), expansion in the 3' UTR of the DMPK gene causes myotonic dystrophy (DM) is unknown. We identified four RNA splicing factors-hnRNP C, U2AF (U2 auxiliary factor), PTB (polypyrimidine tract binding protein), and PSF (PTB associated splicing factor)-that bind to two short regions 3' of the (CUG)(n), and found a novel 3' DMPK exon resulting in an mRNA lacking the repeats. We propose that the (CUG)(n) is an essential cis acting element for this splicing event. In contrast to (CUG)(n) containing mRNAs, the novel isoform is not retained in the nucleus in DM cells, resulting in imbalances in relative levels of cytoplasmic DMPK mRNA isoforms and a new dominant effect of the mutation on DMPK.