Studies have been done to understand how these non-coding mutations could have a trans-dominant effect (i.e. how they could affect 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 mishapen 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:
- Musclebind-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.
- 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 affected genes and the resulting clinical features in the chart below.
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