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

J Med Genet. 2014 Dec;51(12):824-33. doi: 10.1136/jmedgenet-2014-102623.

Johann Böhm ¹, Frédéric Chevessier ², Catherine Koch ¹, G Arielle Peche ¹, Marina Mora ³, Lucia Morandi ⁴, Barbara Pasanisi ⁴, Isabella Moroni ⁵, Giorgio Tasca ⁶, Fabiana Fattori ⁶, Enzo Ricci ⁷, Isabelle Pénisson-Besnier ⁸, Aleksandra Nadaj-Pakleza ⁸, Michel Fardeau ⁹, Pushpa Raj Joshi ¹⁰, Marcus Deschauer ¹⁰, Norma Beatriz Romero ⁹, Bruno Eymard ¹¹, Jocelyn Laporte ¹

Affiliations

1 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.
2 Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany.
3 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.
4 Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
5 Child Neurology Department, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy.
6 Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
7 Institute of Neurology, Catholic University School of Medicine, Rome, Italy.
8 Neurology Department, Centre de Référence des Maladies Neuromusculaires, Centre Hospitalier Universitaire d'Angers, Angers, France.
9 Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France.
10 Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
11 Centre de Référence de Pathologie Neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

PMID: 25326555 DOI: 10.1136/jmedgenet-2014-102623

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.

Keywords

Genetic screening/counselling; Molecular genetics; Muscle disease.

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