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TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both regulating Ca2+ homeostasis through the ubiquitous SOCE (store-operated Ca2+ entry) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ 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- sequencing detected more than 1200 dysregulated genes in Stim1R304W/+ mice and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multi-systemic TAM/STRMK signs, and we identified myostatin as a suitable biomarker for TAM/STRMK in human and mouse. Overall design: We performed RNA-seq on WT, Stim1R304W/+ (Stim1KI),Orai1+/- (Orai1KO), Orai1R93W/+ (Orai1KI), Stim1R304W/+Orai1R93W/+ (Stim1KIOrai1KI), and Stim1R304W/+Orai1+/-(Stim1KIOrai1KO) tibialis anterior muscle samples"],"repository":["ENA"],"additional_accession":[]},"is_claimable":false,"name":"ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome","description":"ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome","dates":{"last_updated":"2025-09-24","first_public":"2024-03-30"},"accession":"PRJNA1023487","cross_references":{"GEO":["GSE244524"],"taxon":["10090"],"PubMed":["38516893"]}}