Store-Operated Ca2+-Entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca 2+ -channels. Gain-of-function mutations of the two key proteins involved, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. At present, no valid treatment is available for these patients. Our group has raised a mouse model bearing the STIM1 p.I115F mutation and has shown that it recapitulates the main features of these gain-of-function disorders: thrombocytopenia and muscle weakness. Similar findings have been found by others in other mouse models bearing a different mutation (p.R304W). Alongside, a drug discovery program to develop modulators of the Orai1 channel was initiated by us that disclosed CIC-39Na as a potent, specific and bioavailable compound. All known gain-of-function mutations (over 20) were shown to be inhibited by this compound. With these tools in hand, we treated wild-type and KI-STIM1I115F mice with CIC-39Na (60 mg/Kg/daily 56days) in constant infusion using micro-pumps and found that both bleeding and muscle weakness could be reverted by this compound. Furthermore, by RNAseq, proteomic analyses and functional studies we have now found that the myopathy is triggered by an abnormal Ca2+-entry, which leads to a decreased storage of Ca2+ in the ER and the subsequent triggering of ER stress and mitochondrial dysfunction, thereby unravelling the pathological cascades downstream of the mutation. CIC-39Na was recently granted orphan designation for tubular aggregate myopathy and these these findinge pave the way to a pharmacological treatment strategy for thrombocytopenia and muscle weakness in tubular aggregate myopathy patients.