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TAM\/STRMK is caused by gain-of-function mutations in the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sensor STIM1 or the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel ORAI1, both of which regulate Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis through the ubiquitous store-operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM\/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    . There is currently no treatment for TAM\/STRMK, but SOCE is amenable to manipulation. Here, we crossed\n                    <jats:italic>\n                      Stim1\n                      <jats:sup>R304W\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice harboring the most common TAM\/STRMK mutation with\n                    <jats:italic>\n                      Orai1\n                      <jats:sup>R93W\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice carrying an ORAI1 mutation partially obstructing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx. Compared with\n                    <jats:italic>\n                      Stim1\n                      <jats:sup>R304W\/+<\/jats:sup>\n                    <\/jats:italic>\n                    littermates,\n                    <jats:italic>\n                      Stim1\n                      <jats:sup>R304W\/+<\/jats:sup>\n                      Orai1\n                      <jats:sup>R93W\/+<\/jats:sup>\n                    <\/jats:italic>\n                    offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in\n                    <jats:italic>\n                      Stim1\n                      <jats:sup>R304W\/+<\/jats:sup>\n                    <\/jats:italic>\n                    muscle and revealed a major restoration of gene expression in\n                    <jats:italic>\n                      Stim1\n                      <jats:sup>R304W\/+<\/jats:sup>\n                      Orai1\n                      <jats:sup>R93W\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM\/STRMK signs, and we identified myostatin as a promising biomarker for TAM\/STRMK in humans and mice.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.174866","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T08:26:26Z","timestamp":1712305586000},"source":"Crossref","is-referenced-by-count":8,"title":["ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0349-4283","authenticated-orcid":true,"given":"Roberto","family":"Silva-Rojas","sequence":"first","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, University of Strasbourg, Illkirch, 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