ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/038/SRR26264638/SRR26264638.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/027/SRR26264627/SRR26264627.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/050/SRR26264650/SRR26264650.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/044/SRR26264644/SRR26264644.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/033/SRR26264633/SRR26264633.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/049/SRR26264649/SRR26264649.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/034/SRR26264634/SRR26264634.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/023/SRR26264623/SRR26264623.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/045/SRR26264645/SRR26264645.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/026/SRR26264626/SRR26264626.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/022/SRR26264622/SRR26264622.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/052/SRR26264652/SRR26264652.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/048/SRR26264648/SRR26264648.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/041/SRR26264641/SRR26264641.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/037/SRR26264637/SRR26264637.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/024/SRR26264624/SRR26264624.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/030/SRR26264630/SRR26264630.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/035/SRR26264635/SRR26264635.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/046/SRR26264646/SRR26264646.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/029/SRR26264629/SRR26264629.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/036/SRR26264636/SRR26264636.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/047/SRR26264647/SRR26264647.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/042/SRR26264642/SRR26264642.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/040/SRR26264640/SRR26264640.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/025/SRR26264625/SRR26264625.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/053/SRR26264653/SRR26264653.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/028/SRR26264628/SRR26264628.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/051/SRR26264651/SRR26264651.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/031/SRR26264631/SRR26264631.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/039/SRR26264639/SRR26264639.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/032/SRR26264632/SRR26264632.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR262/043/SRR26264643/SRR26264643.fastq.gzprimary200OKGenomicsIGBMChttps://www.ebi.ac.uk/ena/browser/view/PRJNA1023487Mus musculusxref:PubMed:38516893Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multi-systemic signs including short stature, thrombocytopenia, and hyposplenism. 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 samplesENAfalseORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndromeORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome2025-09-242024-03-30PRJNA1023487GSE2445241009038516893