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

authors

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

abstract

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.

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