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ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.
Böhm, Johann; Bulla, Monica; Urquhart, Jill E; Malfatti, Edoardo; Williams, Simon G; O'Sullivan, James; Szlauer, Anastazja; Koch, Catherine; Baranello, Giovanni; Mora, Marina; Ripolone, Michela; Violano, Raffaella; Moggio, Maurizio; Kingston, Helen; Dawson, Timothy; DeGoede, Christian G; Nixon, John; Boland, Anne; Deleuze, Jean-François; Romero, Norma; Newman, William G; Demaurex, Nicolas; Laporte, Jocelyn.
Afiliação
  • Böhm J; Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.
  • Bulla M; Inserm, U964, Illkirch, France.
  • Urquhart JE; CNRS, UMR7104, Illkirch, France.
  • Malfatti E; Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France.
  • Williams SG; Collège de France, Chaire de Génétique Humaine, Illkirch, France.
  • O'Sullivan J; Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
  • Szlauer A; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
  • Koch C; Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
  • Baranello G; Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
  • Mora M; Institut de Myologie, GHU La Pitie-Salpetriere, Paris, France.
  • Ripolone M; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
  • Violano R; Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
  • Moggio M; Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
  • Kingston H; Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
  • Dawson T; Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.
  • DeGoede CG; Inserm, U964, Illkirch, France.
  • Nixon J; CNRS, UMR7104, Illkirch, France.
  • Boland A; Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France.
  • Deleuze JF; Collège de France, Chaire de Génétique Humaine, Illkirch, France.
  • Romero N; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
  • Newman WG; Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
  • Demaurex N; Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
  • Laporte J; Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
Hum Mutat ; 38(4): 426-438, 2017 04.
Article em En | MEDLINE | ID: mdl-28058752
ABSTRACT
Calcium (Ca2+ ) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação do Canal Iônico / Mutação de Sentido Incorreto / Miopatias Congênitas Estruturais / Proteína ORAI1 Idioma: En Ano de publicação: 2017 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ativação do Canal Iônico / Mutação de Sentido Incorreto / Miopatias Congênitas Estruturais / Proteína ORAI1 Idioma: En Ano de publicação: 2017 Tipo de documento: Article País de afiliação: França