Abstract

Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.

Details

Title
rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to myotonic dystrophy type 1/type 2 differences
Author
Sellier, Chantal 1 ; Cerro-Herreros, Estefanía 2 ; Blatter, Markus 3 ; Freyermuth, Fernande 1 ; Gaucherot, Angeline 1 ; Ruffenach, Frank 1 ; Sarkar, Partha 4 ; Puymirat, Jack 5 ; Udd, Bjarne 6 ; Day, John W 7 ; Meola, Giovanni 8 ; Bassez, Guillaume 9 ; Fujimura, Harutoshi 10 ; Takahashi, Masanori P 11 ; Schoser, Benedikt 12 ; Furling, Denis 9 ; Artero, Ruben 2   VIAFID ORCID Logo  ; Allain, Frédéric H T 3 ; Llamusi, Beatriz 2 ; Charlet-Berguerand, Nicolas 13 

1  IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France 
2  Translational Genomics Group, Interdisciplinary Research Structure for Biotechnology and Biomedicine BIOTECMED, University of Valencia, Valencia, Spain; INCLIVA Health Research Institute, Valencia, Spain 
3  Institute for Molecular Biology and Biophysics, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland 
4  Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA 
5  Human Genetics Research Unit, Laval University, CHUQ, Ste-Foy, Quebec, Canada 
6  Neuromuscular Research Center, Tampere University Hospital, Tampere, Finland; Department of Medical Genetics, Folkhälsan Institute of Genetics, Helsinki University, Helsinki, Finland; Department of Neurology, Vasa Central Hospital, Vaasa, Finland 
7  Department of Neurology, Stanford University, San Francisco, CA, USA 
8  Department of Biomedical Sciences for Health, University of Milan, Milan, Italy; Neurology Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy 
9  Sorbonne Université, Inserm, Association Institut de Myologie, Center of Research in Myology, Paris, France 
10  Department of Neurology, Toneyama National Hospital, Toyonaka, Japan 
11  Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan 
12  Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilian University, Munich, Germany 
13  IGBMC, INSERM U964, CNRS UMR7104, University of Strasbourg, Illkirch, France; UMR7104, Centre National de la Recherche Scientifique, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France 
Pages
1-15
Publication year
2018
Publication date
May 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-04370-x
ProQuest document ID
2042728668
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.