title: Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1.
abstract: BACKGROUND
  Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or double-walled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene.
  
  
  METHODS
  The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum.
  
  
  RESULTS
  We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EF-hand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adult-onset myalgia without muscle weakness and normal CK levels.
  
  
  CONCLUSIONS
  The present study expands the phenotypical spectrum of STIM1-related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign.
authors.affiliation: Department 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 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 Neuropathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chevessier
authors.affiliation: Department 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 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: Department 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 University of Strasbourg, Illkirch, France Collège de France, Chaire de Génétique Humaine, Illkirch, France.
authors.forename: G Arielle
authors.initials: GA
authors.lastname: Peche
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy Muscle Cell Biology Lab, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pasanisi
authors.affiliation: Child Neurology Department, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tasca
authors.affiliation: Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Fattori
authors.affiliation: Institute of Neurology, Catholic University School of Medicine, Rome, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Ricci
authors.affiliation: Neurology Department, Centre de Référence des Maladies Neuromusculaires, Centre Hospitalier Universitaire d'Angers, Angers, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pénisson-Besnier
authors.affiliation: Neurology Department, Centre de Référence des Maladies Neuromusculaires, Centre Hospitalier Universitaire d'Angers, Angers, France.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Nadaj-Pakleza
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Fardeau
authors.affiliation: Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Pushpa Raj
authors.initials: PR
authors.lastname: Joshi
authors.affiliation: Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Deschauer
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France.
authors.forename: Norma Beatriz
authors.initials: NB
authors.lastname: Romero
authors.affiliation: Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.affiliation: Department 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 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: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D016415:Sequence Alignment; D000071737:Stromal Interaction Molecule 1
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: Genetic screening/counselling; Molecular genetics; Muscle disease