ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy

Hum Mutat. 2017 Apr;38(4):426-438. doi: 10.1002/humu.23172. Epub 2017 Feb 2.

Abstract

Calcium (Ca2+ ) is a physiological key factor, and the precise modulation of free cytosolic Ca2+ levels regulates multiple cellular functions. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling Ca2+ homeostasis, and is mediated by the concerted activity of the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, whereas recessive loss-of-function mutations are associated with immunodeficiency. Here, we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI1 channels, whereas T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggests that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca2+ homeostasis and leading to muscle dysfunction.

Keywords: ORAI1; SOCE; STIM1; Stormorken syndrome; calcium; tubular aggregate myopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Blood Platelet Disorders / genetics
  • Blood Platelet Disorders / metabolism
  • Calcium / metabolism
  • Cells, Cultured
  • Dyslexia / genetics
  • Dyslexia / metabolism
  • Erythrocytes, Abnormal / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Ichthyosis / genetics
  • Ichthyosis / metabolism
  • Ion Channel Gating / genetics*
  • Male
  • Mice, Knockout
  • Microscopy, Fluorescence / methods
  • Migraine Disorders / genetics
  • Migraine Disorders / metabolism
  • Miosis / genetics
  • Miosis / metabolism
  • Muscle Fatigue / genetics
  • Mutation, Missense*
  • Myopathies, Structural, Congenital / genetics*
  • Myopathies, Structural, Congenital / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • ORAI1 Protein / genetics*
  • ORAI1 Protein / metabolism
  • Pedigree
  • Sequence Homology, Amino Acid
  • Spleen / abnormalities
  • Spleen / metabolism
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism

Substances

  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Calcium

Supplementary concepts

  • Stormorken Syndrome