RNA Pathogenesis of Myotonic Dystrophy
Myotonic dystrophy (DM) was the first autosomal dominant disease found to be caused by a repeat expansion that is transcribed into RNA, but is not translated into protein. Transcriptions of the repeat expansion accumulate and, as toxic RNAs, disrupt the function of up to twenty other genes, causing the multiple symptoms of the disorder.
Mutations associated with DM
Two forms of DM (DM1 and DM2) are caused by distinct microsatellite expansions that occur in the non-coding regions of different genes:
- DM1 is an expanded and unstable (CTG)n trinucleotide repeat in the 3’untranslated region of the dystrophia myotonica-protein kinase (DMPK) gene on chromosome 19
- DM2 (also known as proximal myotonic myopathy (PROMM)) is an expanded and unstable (CCTG) n tetranucleotide repeat in the first intron of the zinc finger 9 (Znf9 also known as Cnbp) gene on chromosome 3.
While the DM2 Znf9 gene encodes a nucleic-acid binding protein, its function does not appear to be related to that of the DMPK gene affected in DM1. However, the unusual and rare multisystemic clinical parallels between DM1 and DM2 suggest a similar pathogenic mechanism.
Mechanism of RNA toxicity
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 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:
- 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.
- Cugbp and ETR-3 Like Factors (CELF) - 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. Examples of affected genes and the resulting clinical features include:
- increased inclusion of NMDA NR1 receptor exon 5 (brain dysfunction)
- decreased inclusion of Amyloid Precursor Protein exon 7 (brain dysfunction)
- increased inclusion of Cardiac Troponin T (cTNT or TNNT2) exon 5 (cardiac abnormalities)
- decreased inclusion of Insulin Receptor (IR) exon 11(insulin resistance in muscle and liver)
- 3 defective splice isoforms of Muscle-Specific Chloride Channel CLCN1, each containing a premature termination codon (muscle channelopathy, membrane hyperexcitability and myotonia)
- decreased inclusion of Tau exon 2, 3 and 10 (brain dysfunction)
- 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
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