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Mutation spectrum in the large GTPase dynamin 2, and genotype–phenotype correlation in autosomal dominant centronuclear myopathy

Authors

  • Johann Böhm,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
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  • Valérie Biancalana,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
    2. Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hopital Civil, Strasbourg, France
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  • Elizabeth T. DeChene,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Marc Bitoun,

    1. Institut de Myologie, INSERM U974, University Pierre et Marie Curie UM76, CNRS UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Christopher R. Pierson,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
    Current affiliation:
    1. Nationwide Children's Hospital, Ohio State University, Columbus, Ohio
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  • Elise Schaefer,

    1. Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hopital Civil, Strasbourg, France
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  • Hatice Karasoy,

    1. Department of Neurology, Ege University School of Medicine, Izmir, Turkey
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  • Melissa A. Dempsey,

    1. Human Genetics, The University of Chicago, Chicago, Illinois
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  • Fabrice Klein,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
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  • Nicolas Dondaine,

    1. Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hopital Civil, Strasbourg, France
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  • Christine Kretz,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
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  • Nicolas Haumesser,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
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  • Claire Poirson,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
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  • Anne Toussaint,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
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  • Rebecca S. Greenleaf,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Melissa A. Barger,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Lane J. Mahoney,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Peter B. Kang,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Edmar Zanoteli,

    1. Department of Neurology, Medical School of the University of Sao Paulo Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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  • John Vissing,

    1. Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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  • Nanna Witting,

    1. Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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  • Andoni Echaniz-Laguna,

    1. Department of Neurology, Hopital Civil, Strasbourg, France
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  • Carina Wallgren-Pettersson,

    1. The Folkhälsan Institute of Genetics, Helsinki, Finland
    2. Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland
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  • James Dowling,

    1. Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan
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  • Luciano Merlini,

    1. Laboratory of Musculoskeletal Cell Biology, Instituto Ortopedico Rizzoli, Bologna, Italy
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  • Anders Oldfors,

    1. Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Lilian Bomme Ousager,

    1. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
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  • Judith Melki,

    1. INSERM UMR788, University Paris 11, Hôpital du Kremlin Bicetre, Le Kremlin-Bicetre, France
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  • Amanda Krause,

    1. Division of Human Genetics, National Health Laboratory Service and School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
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  • Christina Jern,

    1. Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
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  • Acary S. B. Oliveira,

    1. Department of Neurology, Federal University of São Paulo, São Paulo, Brazil
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  • Florence Petit,

    1. Service Génétique, Centre Hospitalier Regional Universitaire, Lille, France
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  • Aurélia Jacquette,

    1. Department Génétique, GH Pitié-Salpêtrière, Paris, France
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  • Annabelle Chaussenot,

    1. Service Génétique Médicale, Centre Hospitalier Universitaire Nice, Nice, France
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  • David Mowat,

    1. Department Medical Genetics, Sydney Children's Hospital, Randwick, Australia
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  • Bruno Leheup,

    1. Service de Médecine Infantile III et Génétique Clinique, CHU de Nancy, Nancy, France
    2. Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France
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  • Michele Cristofano,

    1. Department of Neurology, Azienda ospedaliera Pisana, Pisa, Italy
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  • Juan José Poza Aldea,

    1. Servicio de Neurologia, Hospital Donostia, San Sebastian, Spain
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  • Fabrice Michel,

    1. Department of Neuromuscular Investigations and Pathologies, CHU, Besancon, France
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  • Alain Furby,

    1. Service de Neurologie, CHU, Hôpital Nord, Saint Etienne, France
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  • Jose E. Barcena Llona,

    1. Neurologia, Hospital Universitario de Cruces, Baracaldo, Spain
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  • Rudy Van Coster,

    1. Pediatric Neurology, Gent University Hospital, Gent, Belgium
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  • Enrico Bertini,

    1. Department of Neurosciences, Bambino Gesu' Children's Research Hospital, Rome, Italy
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  • Jon Andoni Urtizberea,

    1. Hôpital Marin, Hendaye, France
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  • Valérie Drouin-Garraud,

    1. Service Génétique, Hôpitaux de Rouen, France
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  • Christophe Béroud,

    1. Laboratoire de Génétique Moléculaire, INSERM U827, Montpellier, France
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  • Bernard Prudhon,

    1. Institut de Myologie, INSERM U974, University Pierre et Marie Curie UM76, CNRS UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Melanie Bedford,

    1. Genetics Programme, North York General Hospital, Toronto, Canada
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  • Katherine Mathews,

    1. Carver College of Medicine, University of Iowa, Iowa City, Iowa
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  • Lori A. H. Erby,

    1. Department of Health, Behavior and Society, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
    2. Department of Neurology and Neurosurgery, The John Hopkins School of Medicine, Baltimore, Maryland
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  • Stephen A. Smith,

    1. Hennepin County Medical Center, Minneapolis, Minnesota
    2. Department of Neurology, Gillette Children's Specialty Healthcare, Saint Paul, Minnesota
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  • Jennifer Roggenbuck,

    1. Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota
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  • Carol A. Crowe,

    1. Division of Genetics, MetroHealth Medical Centers, Case Western Reserve University School of Medicine, Cleveland, Ohio
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  • Allison Brennan Spitale,

    1. Division of Genetics, MetroHealth Medical Centers, Case Western Reserve University School of Medicine, Cleveland, Ohio
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  • Sheila C. Johal,

    1. Division of Genetics, MetroHealth Medical Centers, Case Western Reserve University School of Medicine, Cleveland, Ohio
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  • Anthony A. Amato,

    1. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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  • Laurie A. Demmer,

    1. Department of Pediatrics, Tufts Medical Center, Boston, Massachusetts
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  • Jessica Jonas,

    1. Department of Pediatrics, Tufts Medical Center, Boston, Massachusetts
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  • Basil T. Darras,

    1. Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Thomas D. Bird,

    1. Departments of Neurology and Medicine, University of Washington and VA Medical Center, Seattle, Washington
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  • Mercy Laurino,

    1. Department of Medicine, University of Washington, Seattle, Washington
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  • Selman I. Welt,

    1. Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas
    Current affiliation:
    1. Department of Obstetrics and Gynecology, Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
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  • Cynthia Trotter,

    1. Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas
    Current affiliation:
    1. Genzyme Genetics, Westborough, Massachusetts.
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  • Pascale Guicheney,

    1. Institut de Myologie, INSERM U974, University Pierre et Marie Curie UM76, CNRS UMR7215, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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  • Soma Das,

    1. Human Genetics, The University of Chicago, Chicago, Illinois
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  • Jean-Louis Mandel,

    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
    2. Faculté de Médecine, Laboratoire de Diagnostic Génétique, Nouvel Hopital Civil, Strasbourg, France
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  • Alan H. Beggs,

    1. Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts
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  • Jocelyn Laporte

    Corresponding author
    1. Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR7104, University of Strasbourg, Collège de France, Illkirch, France
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, F-67404 Illkirch, France.
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  • Communicated by Arnold Munnich

Abstract

Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. Hum Mutat 33:949–959, 2012. © 2012 Wiley Periodicals, Inc.

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