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In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with
1Department of Biomedicine and Prevention, University 'Tor Vergata', Roma 00133, Italy.
Abstract:
Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway.
Insights
Myotonic dystrophy type-1 (DM1) involves altered RNA splicing and nuclear MBNL1 protein overexpression. This study reveals MBNL142-43 enhances Src kinase activity, suggesting a new phosphotyrosine signaling pathway role in DM1.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Myotonic dystrophy type-1 (DM1) is a prevalent adult muscular dystrophy.
- DM1 is an RNA-dominant disease caused by CTG repeat expansion in the DMPK gene.
- This repeat expansion leads to misregulation of alternative splicing.
Purpose of the Study:
- To investigate the role of specific MBNL1 protein isoforms in DM1 pathogenesis.
- To explore the interaction between MBNL1 and Src family kinases (SFKs).
- To identify novel molecular mechanisms contributing to DM1.
Main Methods:
- Analysis of MBNL1 transcripts and protein isoforms in DM1 muscle.
- In vitro binding assays to study MBNL1-SFK interactions.
- siRNA-mediated knockdown of Exon 5 MBNL1 transcripts.
- Assessment of protein localization and tyrosine phosphorylation levels.
Main Results:
- Overexpression and nuclear localization of MBNL142-43 isoforms in DM1 muscle.
- MBNL142-43 enhances Src family kinase activity through direct binding.
- siRNA targeting Ex5-MBNL142-43 reduced nuclear MBNL1 and Lyn, and decreased tyrosine phosphorylation.
- Confirmation of MBNL1-SFK association in DM1 patient samples.
Conclusions:
- DM1 pathogenesis involves an altered phosphotyrosine signaling pathway.
- MBNL142-43 overexpression contributes to DM1 by enhancing SFK activity.
- Targeting Ex5-MBNL142-43 may offer a therapeutic strategy for DM1.
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