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ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy

Böhm, Johann
Urquhart, Jill E
Malfatti, Edoardo
Williams, Simon G
O'Sullivan, James
Szlauer, Anastazja
Koch, Catherine
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Published in Human Mutation. 2017, vol. 38, no. 4, p. 426-438
Abstract Calcium (Ca(2+) ) is a physiological key factor, and the precise modulation of free cytosolic Ca(2+) levels regulates multiple cellular functions. Store-operated Ca(2+) entry (SOCE) is a major mechanism controlling Ca(2+) homeostasis, and is mediated by the concerted activity of the Ca(2+) sensor STIM1 and the Ca(2+) channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, while 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 ORAI channels, while 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 suggest 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 Ca(2+) homeostasis and leading to muscle dysfunction. This article is protected by copyright. All rights reserved.
PMID: 28058752
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Article (Published version) (1.2 MB) - public document Free access
Research group Signaux intracellulaires (210)
Project FNS: CRSII3_160782
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BÖHM, Johann et al. ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. In: Human Mutation, 2017, vol. 38, n° 4, p. 426-438. https://archive-ouverte.unige.ch/unige:93332

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Deposited on : 2017-04-07

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