title: ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.
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.
authors.affiliation: Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR7104, Illkirch, France.|Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France.|Collège de France, Chaire de Génétique Humaine, Illkirch, France.
authors.forename: Johann
authors.initials: J
authors.lastname: Böhm
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Monica
authors.initials: M
authors.lastname: Bulla
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.|Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|Institut de Myologie, GHU La Pitie-Salpetriere, Paris, France.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.|Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Anastazja
authors.initials: A
authors.lastname: Szlauer
authors.affiliation: Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR7104, Illkirch, France.|Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France.|Collège de France, Chaire de Génétique Humaine, Illkirch, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Koch
authors.affiliation: Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Baranello
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Ripolone
authors.affiliation: Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Violano
authors.affiliation: Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moggio
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.affiliation: Department of Pathology, Royal Preston Hospital, Preston, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Dawson
authors.affiliation: Department of Paediatric Neurology, Royal Preston Hospital, Preston, UK.
authors.forename: Christian G
authors.initials: CG
authors.lastname: DeGoede
authors.affiliation: Department of Neurology, Royal Preston Hospital, Preston, UK.
authors.forename: John
authors.initials: J
authors.lastname: Nixon
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Deleuze
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.|Institut de Myologie, GHU La Pitie-Salpetriere, Paris, France.
authors.forename: Norma
authors.initials: N
authors.lastname: Romero
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester, UK.|Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demaurex
authors.affiliation: Departement of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France.|Inserm, U964, Illkirch, France.|CNRS, UMR7104, Illkirch, France.|Fédération de Médecine Translationnelle, University of Strasbourg, Illkirch, France.|Collège de France, Chaire de Génétique Humaine, Illkirch, France.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001791:Blood Platelet Disorders / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004410:Dyslexia / Q000235:genetics / Q000378:metabolism; D004913:Erythrocytes, Abnormal / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007057:Ichthyosis / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000235:genetics*; D008297:Male; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D008881:Migraine Disorders / Q000235:genetics / Q000378:metabolism; D015877:Miosis / Q000235:genetics / Q000378:metabolism; D018763:Muscle Fatigue / Q000235:genetics; D020125:Mutation, Missense; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013154:Spleen / Q000002:abnormalities / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: ORAI1; SOCE; STIM1; Stormorken syndrome; calcium; tubular aggregate myopathy