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Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1
  1. Johann Böhm1,2,3,4,5,
  2. Frédéric Chevessier6,
  3. Catherine Koch1,2,3,4,5,
  4. G Arielle Peche1,2,3,4,5,
  5. Marina Mora7,8,
  6. Lucia Morandi7,
  7. Barbara Pasanisi7,
  8. Isabella Moroni9,
  9. Giorgio Tasca10,
  10. Fabiana Fattori10,
  11. Enzo Ricci11,
  12. Isabelle Pénisson-Besnier12,
  13. Aleksandra Nadaj-Pakleza12,
  14. Michel Fardeau13,14,
  15. Pushpa Raj Joshi15,
  16. Marcus Deschauer15,
  17. Norma Beatriz Romero13,14,
  18. Bruno Eymard13,
  19. Jocelyn Laporte1,2,3,4,5
  1. 1Department of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France
  2. 2Inserm, U964, Illkirch, France
  3. 3CNRS, UMR7104, Illkirch, France
  4. 4University of Strasbourg, Illkirch, France
  5. 5Collège de France, Chaire de Génétique Humaine, Illkirch, France
  6. 6Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
  7. 7Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy
  8. 8Muscle Cell Biology Lab, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy
  9. 9Child Neurology Department, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy
  10. 10Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy
  11. 11Institute of Neurology, Catholic University School of Medicine, Rome, Italy
  12. 12Neurology Department, Centre de Référence des Maladies Neuromusculaires, Centre Hospitalier Universitaire d'Angers, Angers, France
  13. 13Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
  14. 14Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France
  15. 15Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
  1. Correspondence to Dr Jocelyn Laporte, IGBMC, 1 Rue Laurent Fries, Illkirch 67404, France; jocelyn{at}, Isabelle Pénisson-Besnier died on July 11th, 2013


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.

  • Muscle disease
  • Genetic screening/counselling
  • Molecular genetics

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