PUBLICATION

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Authors

Rau, F., Lainé, J., Ramanoudjame, L., Ferry, A., Arandel, L., Delalande, O., Jollet, A., Dingli, F., Lee, K.Y., Peccate, C., Lorain, S., Kabashi, E., Athanasopoulos, T., Koo, T., Loew, D., Swanson, M.S., Le Rumeur, E., Dickson, G., Allamand, V., Marie, J., Furling, D.

ID

ZDB-PUB-150529-2

Date

2015

Source

Nature communications 6: 7205 (Journal)

Registered Authors

Keywords

none

MeSH Terms

Mice
Microscopy, Electron
Sarcoplasmic Reticulum/ultrastructure
Muscle Proteins/genetics*
Muscle Proteins/metabolism
Chromatography, Liquid
Membrane Proteins/genetics*
Membrane Proteins/metabolism
Immunoprecipitation
Immunohistochemistry
RNA Splicing/genetics*
Dystrophin/genetics*
Dystrophin/metabolism
Exons
RNA-Binding Proteins/genetics*
Animals
Myotonic Dystrophy/genetics*
Myotonic Dystrophy/pathology
Muscle Fibers, Skeletal/metabolism*
Muscle Fibers, Skeletal/ultrastructure
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism
Tandem Mass Spectrometry
Real-Time Polymerase Chain Reaction
Humans
Homeostasis
Gene Expression Regulation, Developmental*

(all 27)

PubMed

26018658 Full text @ Nat. Commun.

Abstract

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Antibody	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
dmd	ab1-dmd	WT	control	Long-pec		vertical myoseptum	IHC	Fig. 2
dmd	ab1-dmd	WT + MO7-dmd	standard conditions	Long-pec		vertical myoseptum	IHC	Fig. 2

1 - 2 of 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO7-dmd	standard conditions	Long-pec	post-vent region decreased length, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	post-vent region kinked, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	skeletal muscle cell myofibril disorganized, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	skeletal muscle tissue development disrupted, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	slow muscle cell detached from vertical myoseptum, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	startle response process quality, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	swimming behavior process quality, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	thigmotaxis process quality, abnormal	Fig. 2
WT + MO7-dmd	standard conditions	Long-pec	vertical myoseptum U-shaped, abnormal	Fig. 2

1 - 9 of 9

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Mutations / Transgenics

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
myotonic dystrophy type 1			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
dmd	MO7-dmd	MRPHLNO

Fish

Fish
WT
WT + MO7-dmd

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-dmd	monoclonal	dmd	IgG1	Mouse
Ab-F59	monoclonal		IgG1	Mouse

Orthology

Engineered Foreign Genes

Mapping

Rau et al., 2015 ZDB-PUB-150529-2 PMID:26018658

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Rau et al., 2015

ZDB-PUB-150529-2
PMID:26018658