RNA toxicity Studies have been done to understand how these non-coding mutations could have a trans-dominant eect (i.e. how they could aect other genes not associated with the mutation locus). This research suggests a gain-of-function RNA mechanism underlies the clinical features common to both diseases. In both forms of myotonic dystrophy, RNAs transcribed from the genes have unusually long repeats of either CUG (DM1) or CCUG (DM2). The nucleotide repeats cause the RNA strands to develop abnormal hairpin folds. These misshaped RNA structures then bind splice-regulating proteins, forming RNA-protein complexes that accumulate within nuclei. These nuclear foci can disrupt biological function by altering the available amounts of two classes of RNA-binding splice regulators: t Muscleblind-like (Mbnl) proteins (Mbnl1, Mbnll and Mbxl). Mbnl splice regulators are sequestered in the nuclear foci, resulting in nuclear depletion and a loss of function. t Cugbp and ETR-3 Like Factors (CELF). The expression of Cugbp1 is increased through a signaling event that results in its phosphorylation and stabilization. The disruption of these splice regulators interferes with the processing of transcripts in more than twenty other genes. In all cases, the aberrant splicing results in abnormal developmental processing where embryonic isoforms of the resulting proteins are expressed in adult myotonic dystrophy tissues. The immature proteins then appear to cause the clinical features common to both diseases. See examples of aected genes and the resulting clinical features in the chart below. Clinical feature Gene abnormalities Increased inclusion of NMDA NR1 receptor exon 5 Brain dysfunction Decreased inclusion of Amyloid Precursor Protein exon 7 Decreased inclusion of Tau exon 2, 3 and 10 Increased inclusion of Cardiac Troponin T (cTNT or Cardiac abnormalities TNNT2) exon 5 Insulin resistance in muscle and liver Decreased inclusion of Insulin Receptor (IR) exon 11 3 defective splice isoforms of Muscle-Specic Muscle channelopathy, membrane hyperexcitability, Chloride Channel CLCN1, each containing a premature and myotonia termination codon Increased inclusion of fetal isoforms A and B of the Myotubularin-related 1 (MTMR1) gene Muscle atrophy Decreased inclusion of Dystrophin exon 71 or 78 42 MYOTONIC DYSTROPHY FOUNDATION | TOOLKIT.