Constitutive activation of the calcium sensor STIM1 causes tubular-aggregate myopathy

Am J Hum Genet. 2013 Feb 7;92(2):271-8. doi: 10.1016/j.ajhg.2012.12.007. Epub 2013 Jan 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Calcium / metabolism*
  • Cell Line
  • Child
  • Female
  • Homeostasis
  • Humans
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Muscles / pathology
  • Muscles / ultrastructure
  • Mutation / genetics
  • Myoblasts / metabolism
  • Myoblasts / pathology
  • Myopathies, Structural, Congenital / genetics
  • Myopathies, Structural, Congenital / pathology*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Pedigree
  • Phenotype
  • Stromal Interaction Molecule 1
  • Young Adult


  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Calcium