title: Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy.
abstract: Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.
authors.affiliation: IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.forename: Nasim
authors.initials: N
authors.lastname: Vasli
authors.forename: Marie
authors.initials: M
authors.lastname: Maurer
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Cowling
authors.forename: Belinda
authors.initials: B
authors.lastname: Cowling
authors.forename: G Diane
authors.initials: GD
authors.lastname: Shelton
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.forename: Anne
authors.initials: A
authors.lastname: Toussaint
authors.forename: Ivana
authors.initials: I
authors.lastname: Prokic
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Thomas James
authors.initials: TJ
authors.lastname: Anderson
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Laurent
authors.initials: L
authors.lastname: Tiret
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004285:Dogs; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000662:veterinary; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D009928:Organ Specificity; D022821:RNA Splice Sites / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D022821:RNA Splice Sites; D025521:Tumor Suppressor Proteins