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RNA misprocessing causes muscle weakness disorder
Both myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) can be explained by the DMPK gene becoming longer than normal. This happens when a longer than normal RNA strand is produced, consisting of repeated chemical sequences of CUG — or cytosine, uracil, and guanine. In the process of identifying how this mechanism goes wrong, researchers also developed a mouse model to allow them to test potential drug therapies.
The findings are published in the journal Genes & Development.
The disorder leads to severe muscle weakness. But, congenital myotonic dystrophy patients can also have respiratory problems and intellectual deficits. It is estimated to affect one in every 16,000 births. Misregulation by genetic "switches," the chemical interactions controlling when and how genes function, is believed to be at fault. The interruption in gene function distorts in-utero muscle development, according to Maurice Swanson PhD, professor in the department of molecular genetics and microbiology, University of Florida (UF), College of Medicine.
"The ultimate goal is to come up with ideas for treating children with this disease soon after birth and minimize the long-term effects of the disorder."
Messenger RNA molecules receive instructions from DNA to carry out protein-building activities. Testing on human muscle tissue, researchers found severe RNA misprocessing by mutant RNA is a major cause of congenital muscular dystrophy. Specifically, they identified several abnormalities in the genetic coding process that gives rise to the disease, including one that causes a single gene to produce multiple proteins. In the mouse model which mimics the disease, researchers found disruption of a particular protein during prenatal development, results in muscle disorders at birth.
All the results point to a disruption in certain RNA processes — before birth — that alter gene switches essential in muscle formation.
"This provides us important new information about where we should go next and what kinds of therapeutics might be effective against this hereditary disease," Swanson adds. This is as significant as knowing where and when congenital errors arise in genes, and is an important first step on the road to better management — and maybe a potential cure.
Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTGexp) disorder caused by expression of CUGexp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUGexp-associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.
Keywords: congenital myotonic dystrophy, MBNL, microsatellite myoblast myogenesis, RNA processing
Researchers from the Osaka University Graduate School of Medicine in Osaka, Japan, collaborated on the research. The study was supported by the National Institutes of Health, the Japan Society for the Promotion of Science, and the Myotonic Dystrophy and Wyck foundations.
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