title: Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy.
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 Ca(2+) sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca(2+)-binding EF hands. Ca(2+) stores are refilled through a process called store-operated Ca(2+) entry (SOCE). Upon Ca(2+)-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca(2+) entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca(2+) sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca(2+) level in TAM cells and a dysregulation of intracellular Ca(2+) 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.
authors: Département de Médecine Translationelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
authors: Johann
authors: J
authors: Böhm
authors: Frédéric
authors: F
authors: Chevessier
authors: André
authors: A
authors: Maues De Paula
authors: Catherine
authors: C
authors: Koch
authors: Shahram
authors: S
authors: Attarian
authors: Claire
authors: C
authors: Feger
authors: Daniel
authors: D
authors: Hantaï
authors: Pascal
authors: P
authors: Laforêt
authors: Karima
authors: K
authors: Ghorab
authors: Jean-Michel
authors: JM
authors: Vallat
authors: Michel
authors: M
authors: Fardeau
authors: Dominique
authors: D
authors: Figarella-Branger
authors: Jean
authors: J
authors: Pouget
authors: Norma B
authors: NB
authors: Romero
authors: Marc
authors: M
authors: Koch
authors: Claudine
authors: C
authors: Ebel
authors: Nicolas
authors: N
authors: Levy
authors: Martin
authors: M
authors: Krahn
authors: Bruno
authors: B
authors: Eymard
authors: Marc
authors: M
authors: Bartoli
authors: Jocelyn
authors: J
authors: Laporte
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002648:Child; D005260:Female; D006706:Homeostasis; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009132:Muscles / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000473:pathology*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D000071737:Stromal Interaction Molecule 1; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium