Böhm, J;
Bulla, M;
Urquhart, JE;
Malfatti, E;
Williams, SG;
O'Sullivan, J;
Szlauer, A;
... Laporte, J; + view all
(2017)
ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.
Human Mutation
, 38
(4)
pp. 426-438.
10.1002/humu.23172.
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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.
| Type: | Article |
|---|---|
| Title: | ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1002/humu.23172 |
| Publisher version: | https://doi.org/10.1002/humu.23172 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | tubular aggregate myopathy, Stormorken syndrome, ORAI1, calcium, SOCE, STIM1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10067486 |
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