title: Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations.
abstract: Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.
authors.affiliation: 1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.affiliation: 1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France 6 Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, 67000 Strasbourg, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.affiliation: 7 Université Paris 6 UM76, Inserm UMR 974, CNRS UMR 7215, Institut de Myologie, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France 8 Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France 9 Department of Neurological, Neurosurgical, and Behavioural Sciences, University of Siena, 53100 Siena, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.affiliation: 6 Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, 67000 Strasbourg, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dondaine
authors.affiliation: 1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Koch
authors.affiliation: 1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France.
authors.forename: Nasim
authors.initials: N
authors.lastname: Vasli
authors.affiliation: 10 Department of Human Genetics, Julius-Maximilian University, 97074 Würzburg, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Kress
authors.affiliation: 11 Neurology, SHG Klinikum, 66663 Merzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Strittmatter
authors.affiliation: 12 Institute for Neurological Research, FLENI, C1428AQK Buenos Aires, Argentina.
authors.forename: Ana Lia
authors.initials: AL
authors.lastname: Taratuto
authors.affiliation: 13 Hospital Italiano de Buenos Aires, C1181ACH Buenos Aires, Argentina.
authors.forename: Hernan
authors.initials: H
authors.lastname: Gonorazky
authors.affiliation: 8 Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforêt
authors.affiliation: 14 Laboratoire de Neuropathologie, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.affiliation: 15 Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, 08901 Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.affiliation: 15 Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, 08901 Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Gonzalez-Mera
authors.affiliation: 7 Université Paris 6 UM76, Inserm UMR 974, CNRS UMR 7215, Institut de Myologie, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France 8 Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.affiliation: 16 Inserm, U929, 63000 Clermont-Ferrand, France 17 Université Clermont 1, 63000 Clermont-Ferrand, France 18 CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Carrière
authors.affiliation: 16 Inserm, U929, 63000 Clermont-Ferrand, France 17 Université Clermont 1, 63000 Clermont-Ferrand, France 18 CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Clavelou
authors.affiliation: 8 Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.affiliation: 7 Université Paris 6 UM76, Inserm UMR 974, CNRS UMR 7215, Institut de Myologie, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Bitoun
authors.affiliation: 19 Département de Biochimie, Biochimie et Génétique Moléculaire, Toxicologie et Pharmacologie, CHU Grenoble, 38700 La Tronche, France.
authors.forename: John
authors.initials: J
authors.lastname: Rendu
authors.affiliation: 19 Département de Biochimie, Biochimie et Génétique Moléculaire, Toxicologie et Pharmacologie, CHU Grenoble, 38700 La Tronche, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Fauré
authors.affiliation: 20 Institute of Neuropathology and JARA Brain Translational Medicine, RWTH Aachen University, 52062 Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.affiliation: 1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France 6 Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, 67000 Strasbourg, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.affiliation: 7 Université Paris 6 UM76, Inserm UMR 974, CNRS UMR 7215, Institut de Myologie, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France 8 Centre de référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier La Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.affiliation: 1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France jocelyn@igbmc.fr.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D034285:Dynamin II / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D034285:Dynamin II
keywords: BIN1; DNM2; T-tubule; amphiphysin 2; centronuclear myopathy