Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.
Charlotte Fugier
(1)
,
Arnaud F Klein
(2)
,
Caroline Hammer
(1)
,
Stéphane Vassilopoulos
(2)
,
Ylva Ivarsson
(3)
,
Anne Toussaint
(1)
,
Valérie Tosch
(4)
,
Alban Vignaud
(5)
,
Arnaud Ferry
(5)
,
Nadia Messaddeq
(4)
,
Yosuke Kokunai
,
Rie Tsuburaya
,
Pierre de La Grange
(6)
,
Doulaye Dembele
(4)
,
Virginie Francois
(5)
,
Guillaume Precigout
(5)
,
Charlotte Boulade-Ladame
(7)
,
Marie-Christine Hummel
,
Adolfo Lopez de Munain
,
Nicolas Sergeant
(8)
,
Annie Laquerrière
(9)
,
Christelle Thibault
(4)
,
François Deryckere
(7)
,
Didier Auboeuf
(10)
,
Luis Garcia
(5)
,
Pascale Zimmermann
(11, 12)
,
Bjarne Udd
(13)
,
Benedikt Schoser
,
Masanori P Takahashi
,
Ichizo Nishino
,
Guillaume Bassez
(14, 15)
,
Jocelyn Laporte
(4)
,
Denis Furling
(2)
,
Nicolas Charlet-Berguerand
(1)
1
IGBMC -
Institut de génétique et biologie moléculaire et cellulaire
2 Centre de recherche en Myologie – U974 SU-INSERM
3 Department of Biochemical Sciences "Rossi Fanelli"
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 Thérapie des maladies du muscle strié
6 GenoSplice Technology
7 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique
8 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
9 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
10 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
11 IPC - Institut Paoli-Calmettes
12 CRCM / U891 Inserm - Centre de Recherche en Cancérologie de Marseille
13 Neurology Department
14 Département de pathologie [Mondor]
15 IMRB - Institut Mondor de Recherche Biomédicale
2 Centre de recherche en Myologie – U974 SU-INSERM
3 Department of Biochemical Sciences "Rossi Fanelli"
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 Thérapie des maladies du muscle strié
6 GenoSplice Technology
7 Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique
8 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837
9 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
10 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
11 IPC - Institut Paoli-Calmettes
12 CRCM / U891 Inserm - Centre de Recherche en Cancérologie de Marseille
13 Neurology Department
14 Département de pathologie [Mondor]
15 IMRB - Institut Mondor de Recherche Biomédicale
Arnaud F Klein
- Function : Author
- PersonId : 1081407
- IdHAL : arnaud-f-klein
- ORCID : 0000-0002-3860-7049
Stéphane Vassilopoulos
- Function : Author
- PersonId : 740750
- IdHAL : stephane-vassilopoulos
- ORCID : 0000-0003-0172-330X
- IdRef : 112843905
Arnaud Ferry
- Function : Author
- PersonId : 938065
- IdHAL : arnaud-ferry
Nadia Messaddeq
- Function : Author
- PersonId : 756041
- ORCID : 0000-0001-8398-6415
Yosuke Kokunai
- Function : Author
Rie Tsuburaya
- Function : Author
Doulaye Dembele
- Function : Author
- PersonId : 762775
- ORCID : 0000-0003-3879-6940
Marie-Christine Hummel
- Function : Author
Adolfo Lopez de Munain
- Function : Author
Didier Auboeuf
- Function : Author
- PersonId : 1147387
- ORCID : 0000-0002-3757-0002
- IdRef : 128682663
Benedikt Schoser
- Function : Author
Masanori P Takahashi
- Function : Author
Ichizo Nishino
- Function : Author
Guillaume Bassez
- Function : Author
- PersonId : 1196296
- IdHAL : guillaume-bassez
Jocelyn Laporte
- Function : Author
- PersonId : 181385
- IdHAL : jocelyn-laporte
- ORCID : 0000-0001-8256-5862
- IdRef : 131835262
Denis Furling
- Function : Author
- PersonId : 744465
- IdHAL : denis-furling
- ORCID : 0000-0001-7912-4409
- IdRef : 167401556
Nicolas Charlet-Berguerand
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- Function : Correspondent author
- PersonId : 748210
- IdHAL : nicolas-charlet-berguerand
- ORCID : 0000-0002-4423-4920
- IdRef : 089052471
Connectez-vous pour contacter l'auteur
Abstract
Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.