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                <term xml:lang="en">Calcium</term>
                <term xml:lang="en">Stormorken syndrome</term>
                <term xml:lang="en">Tubular aggregate myopathy</term>
                <term xml:lang="fr">ORAI1</term>
                <term xml:lang="fr">STIM1</term>
                <term xml:lang="fr">Calcium</term>
                <term xml:lang="fr">Syndrome de Stormorken</term>
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              <p>Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders caused by gain-of-function mutations in STIM1 and ORAI1 inducing excessive extracellular Ca2+ entry. The precise molecular pathomechanisms leading to the multi-systemic clinical picture remain however unknown, and no therapy is currently available. In order to identify the pathological effects of STIM1 over-activation, we generated a mouse model carrying the most common TAM/STRMK mutation, and Stim1R304W/+ mice recapitulated the main signs of the disease. I also showed that cellular Ca2+ overload interferes with proper muscle contraction and relaxation, and induces sustained reticular stress and muscle fiber degeneration. Finally, I explored therapeutic approaches to treat TAM/STRMK.</p>
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              <p>Résumé en français suivi des mots-clés en françaisLa myopathie à agrégats tubulaires (TAM) et le syndrome de Stormorken (STRMK) forment un spectre clinique dû à des mutations de gain de fonction dans les gènes STIM1 et ORAI1 menant à l’entrée excessive de Ca2+ extracellulaire. Les mécanismes pathologiques menant aux défauts multi-systémiques restent à élucider et aucune thérapie n’est disponible. Afin d’éclairer les effets pathologiques de la sur-activation de STIM1, nous avons généré un modèle murin portant la mutation TAM/STRMK la plus commune, et les souris Stim1R304W/+ ont récapitulé les signes majeurs de la maladie. J’ai également montré que la surcharge de Ca2+ cellulaire interfère avec la contraction et relaxation musculaire, induit du stress réticulaire et de la dégénérescence musculaire. Enfin, j’ai exploré des approches thérapeutiques visant à traiter TAM/STRMK.</p>
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