A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice
Store-operated Ca<sup>2+</sup> entry (SOCE) controls Ca<sup>2+</sup> homeostasis and mediates multiple Ca<sup>2+</sup>-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca<sup>2+</sup> sensor STIM...
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2024-11-01
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| author | Laura Pérez-Guàrdia Emma Lafabrie Nadège Diedhiou Coralie Spiegelhalter Jocelyn Laporte Johann Böhm |
| author_facet | Laura Pérez-Guàrdia Emma Lafabrie Nadège Diedhiou Coralie Spiegelhalter Jocelyn Laporte Johann Böhm |
| author_sort | Laura Pérez-Guàrdia |
| collection | DOAJ |
| description | Store-operated Ca<sup>2+</sup> entry (SOCE) controls Ca<sup>2+</sup> homeostasis and mediates multiple Ca<sup>2+</sup>-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca<sup>2+</sup> sensor STIM1 and the plasma membrane Ca<sup>2+</sup> channel ORAI1. STIM1 and ORAI1 gain-of-function (GoF) mutations induce SOCE overactivity and excessive Ca<sup>2+</sup> influx, leading to tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and a variable occurrence of multi-systemic anomalies affecting spleen, skin, and platelets. To date, different STIM1 mouse models exist, but only a single ORAI1 mouse model with muscle-specific TAM/STRMK phenotype has been described, precluding a comparative analysis of the physiopathology in all affected tissues. Here, we generated and characterized mice harboring a prevalent ORAI1 TAM/STRMK mutation and we provide phenotypic, physiological, biochemical, and functional data. Examination of <i>Orai1<sup>V109M/+</sup></i> mice revealed smaller size, spleen enlargement, reduced muscle force, and decreased platelet numbers. Morphological analyses of muscle sections evidenced the presence of tubular aggregates, the histopathological hallmark on biopsies from TAM/STRMK patients absent in all reported STIM1 models. Overall, <i>Orai1<sup>V109M/+</sup></i> mice reliably recapitulate the human disorder and highlight the primary physiological defects caused by ORAI1 gain-of-function mutations. They also provide the possibility to investigate the formation of tubular aggregates and to develop a common therapy for different TAM/STRMK forms. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2024-11-01 |
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| series | Cells |
| spelling | doaj-art-433bc148b6a54aa5a066d77dc9c3a24e2024-11-26T17:56:42ZengMDPI AGCells2073-44092024-11-011322182910.3390/cells13221829A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in MiceLaura Pérez-Guàrdia0Emma Lafabrie1Nadège Diedhiou2Coralie Spiegelhalter3Jocelyn Laporte4Johann Böhm5Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, FranceStore-operated Ca<sup>2+</sup> entry (SOCE) controls Ca<sup>2+</sup> homeostasis and mediates multiple Ca<sup>2+</sup>-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca<sup>2+</sup> sensor STIM1 and the plasma membrane Ca<sup>2+</sup> channel ORAI1. STIM1 and ORAI1 gain-of-function (GoF) mutations induce SOCE overactivity and excessive Ca<sup>2+</sup> influx, leading to tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and a variable occurrence of multi-systemic anomalies affecting spleen, skin, and platelets. To date, different STIM1 mouse models exist, but only a single ORAI1 mouse model with muscle-specific TAM/STRMK phenotype has been described, precluding a comparative analysis of the physiopathology in all affected tissues. Here, we generated and characterized mice harboring a prevalent ORAI1 TAM/STRMK mutation and we provide phenotypic, physiological, biochemical, and functional data. Examination of <i>Orai1<sup>V109M/+</sup></i> mice revealed smaller size, spleen enlargement, reduced muscle force, and decreased platelet numbers. Morphological analyses of muscle sections evidenced the presence of tubular aggregates, the histopathological hallmark on biopsies from TAM/STRMK patients absent in all reported STIM1 models. Overall, <i>Orai1<sup>V109M/+</sup></i> mice reliably recapitulate the human disorder and highlight the primary physiological defects caused by ORAI1 gain-of-function mutations. They also provide the possibility to investigate the formation of tubular aggregates and to develop a common therapy for different TAM/STRMK forms.https://www.mdpi.com/2073-4409/13/22/1829myopathycalciumStormorken syndromeORAI1STIM1SOCE |
| spellingShingle | Laura Pérez-Guàrdia Emma Lafabrie Nadège Diedhiou Coralie Spiegelhalter Jocelyn Laporte Johann Böhm A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice Cells myopathy calcium Stormorken syndrome ORAI1 STIM1 SOCE |
| title | A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice |
| title_full | A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice |
| title_fullStr | A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice |
| title_full_unstemmed | A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice |
| title_short | A Gain-of-Function Mutation in the Ca<sup>2+</sup> Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice |
| title_sort | gain of function mutation in the ca sup 2 sup channel orai1 causes stormorken syndrome with tubular aggregates in mice |
| topic | myopathy calcium Stormorken syndrome ORAI1 STIM1 SOCE |
| url | https://www.mdpi.com/2073-4409/13/22/1829 |
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