 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Dec 01, 2013 |
| Title |
Compound loss of muscleblind-like function in myotonic dystrophy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Myotonic dystrophy (DM) is a multi-systemic disease that severely impacts cardiac and skeletal muscle functions as well as the central nervous system. DM is unusual because it is RNA-mediated disease due to the expression of C(C)UG expansion RNAs that inhibit the activities of the muscleblind-like (MBNL) proteins. In mice, studies using Mbnl1 and Mbnl2 single knockouts have revealed that Mbnl1 plays a predominant role in skeletal and heart muscle alternative splicing regulation while Mbnl2 performs an analogous splicing function in the brain. However, Mbnl single knockout models fail to recapitulate the full-range of adult-onset DM muscle symptoms. Here, we report that Mbnl1; Mbnl2 double knockouts are embryonic lethal while Mbnl1-/-; Mbnl2+/- mice, which express no Mbnl1 and reduced levels of Mbnl2, are viable but develop cardinal features of adult-onset DM cardiac and skeletal muscle disease including reduced lifespan, heart conduction block, severe myotonia and progressive skeletal muscle weakness. Mbnl2 protein levels are elevated in both Mbnl1-/- and Mbnl1-/-; Mbnl2+/- knockouts where Mbnl2 targets Mbnl1-regulated exons. These findings support the MBNL loss-of-function model for DM and provide novel Mbnl compound knockout models to investigate the molecular pathways disrupted by RNA-mediated disease.
|
| |
|
| Overall design |
Mbnl2 protein-RNA interactions were assessed in 4-month-old WT and Mbnl1-/- quadriceps muscles in triplicates by HITS-CLIP.
|
| |
|
| Contributor(s) |
Manchanda M |
| Citation(s) |
24293317 |
| Submission date |
Jun 10, 2013 |
| Last update date |
May 15, 2019 |
| Contact name |
Maurice Swanson |
| E-mail(s) |
mswanson@ufl.edu
|
| Phone |
3522738076
|
| Organization name |
University of Florida
|
| Department |
Molecular Genetics and Microbiology
|
| Lab |
220G
|
| Street address |
2033 Mowry Road
|
| City |
Gainesville |
| State/province |
Fl |
| ZIP/Postal code |
32608 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL11002 |
Illumina Genome Analyzer IIx (Mus musculus) |
|
| Samples (2) |
|
| Relations |
| BioProject |
PRJNA207816 |
| SRA |
SRP024393 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE47794_RAW.tar |
12.8 Mb |
(http)(custom) |
TAR (of BED) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
