Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy.
Genes Dev
; 31(11): 1122-1133, 2017 06 01.
Article
in En
| MEDLINE
| ID: mdl-28698297
ABSTRACT
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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
RNA Processing, Post-Transcriptional
/
RNA Splicing
/
RNA-Binding Proteins
/
Muscle Development
/
Myotonic Dystrophy
Type of study:
Prognostic_studies
Limits:
Animals
/
Child, preschool
/
Humans
/
Infant
Language:
En
Journal:
Genes Dev
Journal subject:
BIOLOGIA MOLECULAR
Year:
2017
Type:
Article
Affiliation country:
United States