Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1

Johann Böhm, Frédéric Chevessier, Catherine Koch, G. Arielle Peche, Marina Mora, Lucia Morandi, Barbara Pasanisi, Isabella Moroni, Giorgio Tasca, Fabiana Fattori, Enzo Ricci, Isabelle Pénisson-Besnier, Aleksandra Nadaj-Pakleza, Michel Fardeau, Pushpa Raj Joshi, Marcus Deschauer, Norma Beatriz Romero, Bruno Eymard, Jocelyn Laporte

Research output: Contribution to journalArticlepeer-review


Background: Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or doublewalled 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 EFhand 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 adultonset 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.

Original languageEnglish
Pages (from-to)824-833
Number of pages10
JournalJournal of Medical Genetics
Issue number12
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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