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Hum Mol Genet. 2018 Dec 21. doi: 10.1093/hmg/ddy446. [Epub ahead of print]

STIM1 over-activation generates a multi-systemic phenotype affecting skeletal muscle, spleen, eye, skin, bones, and the immune system in mice.

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IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France.
Departments of Biomedicine and Anaesthesia, Basel University Hospital, Basel University, 4031 Basel, Switzerland.
Institut Clinique de la Souris (ICS), 67404 Illkirch, France.


Strict regulation of Ca2+ homeostasis is essential for normal cellular physiology. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling basal Ca2+ levels and intracellular Ca2+ store refilling, and abnormal SOCE severely impacts on human health. Overactive SOCE results in excessive extracellular Ca2+ entry due to dominant STIM1 or ORAI1 mutations, and has been associated with tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). Both disorders are spectra of the same disease and involve muscle weakness, myalgia, and cramps, and additional multi-systemic signs including miosis, bleeding diathesis, hyposplenism, dyslexia, short stature, and ichthyosis. To elucidate the physiological consequences of STIM1 over-activation, we generated a murine model harboring the most common TAM/Stormorken syndrome mutation and characterized the phenotype at the histological, ultrastructural, metabolic, physiological, and functional level. In accordance with the clinical picture of TAM/Stormorken syndrome, the Stim1R304W/+ mice manifested muscle weakness, thrombocytopenia, skin and eye anomalies, and spleen dysfunction, as well as additional features not yet observed in patients such as abnormal bone architecture and immune system dysregulation. The murine muscles exhibited contraction and relaxation defects as well as dystrophic features, and functional investigations unraveled increased Ca2+ influx in myotubes. In conclusion, we provide insight into the pathophysiological effect of the STIM1 R304W mutation in different cells, tissues, and organs, and thereby significantly contribute to a deeper understanding of the pathomechanisms underlying TAM/Stormorken syndrome and other human disorders involving aberrant Ca2+ homeostasis and affecting muscle, bones, platelets, or the immune system.


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