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Title: Misregulated alternative splicing of BIN1 is associated with T tubule alterations and muscle weakness in myotonic dystrophy
Authors: Fugier, Charlotte
Klein, Arnaud F
Hammer, Caroline
Vassilopoulos, Stéphane
Ivarsson, Ylva
Toussaint, Anne
Tosch, Valérie
Vignaud, Alban
Ferry, Arnaud
Messaddeq, Nadia
Kokunai, Yosuke
Tsuburaya, Rie
de la Grange, Pierre
Dembele, Doulaye
Francois, Virginie
Precigout, Guillaume
Boulade-Ladame, Charlotte
Hummel, Marie-Christine
Lopez de Munain, Adolfo
Sergeant, Nicolas
Laquerrière, Annie
Thibault, Christelle
Deryckere, François
Auboeuf, Didier
Garcia, Luis
Zimmermann, Pascale
Udd, Bjarne
Schoser, Benedikt
Takahashi, Masanori P
Nishino, Ichizo
Bassez, Guillaume
Laporte, Jocelyn
Furling, Denis
Charlet-Berguerand, Nicolas # ×
Issue Date: Jun-2011
Publisher: Nature Pub. Co.
Series Title: Nature Medicine vol:17 issue:6 pages:720-U112
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.
URI: 
ISSN: 1078-8956
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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