title: Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.
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.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U964, Centre National de la Recherche Scientifique UMR7104, University of Strasbourg, Illkirch, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Fugier
authors.forename: Arnaud F
authors.initials: AF
authors.lastname: Klein
authors.forename: Caroline
authors.initials: C
authors.lastname: Hammer
authors.forename: Stéphane
authors.initials: S
authors.lastname: Vassilopoulos
authors.forename: Ylva
authors.initials: Y
authors.lastname: Ivarsson
authors.forename: Anne
authors.initials: A
authors.lastname: Toussaint
authors.forename: Valérie
authors.initials: V
authors.lastname: Tosch
authors.forename: Alban
authors.initials: A
authors.lastname: Vignaud
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kokunai
authors.forename: Rie
authors.initials: R
authors.lastname: Tsuburaya
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.forename: Doulaye
authors.initials: D
authors.lastname: Dembele
authors.forename: Virginie
authors.initials: V
authors.lastname: Francois
authors.forename: Guillaume
authors.initials: G
authors.lastname: Precigout
authors.forename: Charlotte
authors.initials: C
authors.lastname: Boulade-Ladame
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Hummel
authors.forename: Adolfo
authors.initials: A
authors.lastname: Lopez de Munain
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerrière
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: François
authors.initials: F
authors.lastname: Deryckere
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
authors.forename: Pascale
authors.initials: P
authors.lastname: Zimmermann
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bassez
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D005091:Exons / Q000235:genetics; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018908:Muscle Weakness / Q000235:genetics* / Q000503:physiopathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; C493663:MBNL1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins