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Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

By Johann Böhm, Frédéric Chevessier, André Maues De Paula, Catherine Koch, Shahram Attarian, Claire Feger, Daniel Hantaï, Pascal Laforêt, Karima Ghorab, Jean-Michel Vallat, Michel Fardeau, Dominique Figarella-Branger, Jean Pouget, Norma B. Romero, Marc Koch, Claudine Ebel, Nicolas Levy, Martin Krahn, Bruno Eymard, Marc Bartoli and Jocelyn Laporte


Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca2+ sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca2+-binding EF hands. Ca2+ stores are refilled through a process called store-operated Ca2+ entry (SOCE). Upon Ca2+-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca2+ entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca2+ sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca2+ level in TAM cells and a dysregulation of intracellular Ca2+ homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function

Publisher: The American Society of Human Genetics. Published by Elsevier Inc.
Year: 2013
DOI identifier: 10.1016/j.ajhg.2012.12.007
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