Skip to Main content Skip to Navigation
Journal articles

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 2 Stéphane Vassilopoulos 3 Ylva Ivarsson 4 Anne Toussaint 5 Valérie Tosch 2 Alban Vignaud 6 Arnaud Ferry 6 Nadia Messaddeq 2 Yosuke Kokunai Rie Tsuburaya Pierre de la Grange 7 Doulaye Dembele 2 Virginie Francois Guillaume Precigout Charlotte Boulade-Ladame 8 Marie-Christine Hummel Adolfo Lopez de Munain Nicolas Sergeant 9 Annie Laquerrière 10 Christelle Thibault 2 François Deryckere 8 Didier Auboeuf 11 Luis Garcia 6 Pascale Zimmermann 12, 13, 14 Bjarne Udd 15 Benedikt Schoser Masanori P Takahashi Ichizo Nishino Guillaume Bassez 16, 17 Jocelyn Laporte 2 Denis Furling 6 Nicolas Charlet-Berguerand 5, *
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.
Document type :
Journal articles
Complete list of metadata
Contributor : Marie-Pierre Scanella Connect in order to contact the contributor
Submitted on : Thursday, April 11, 2013 - 2:43:24 PM
Last modification on : Tuesday, October 19, 2021 - 11:07:57 PM



Charlotte Fugier, Arnaud F Klein, Caroline Hammer, Stéphane Vassilopoulos, Ylva Ivarsson, et al.. Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy.. Nature Medicine, Nature Publishing Group, 2011, 17 (6), pp.720-5. ⟨10.1038/nm.2374⟩. ⟨hal-00811986⟩



Record views