Ca2+ is a major regulatory and signaling molecule in skeletal muscle, therefore the cellular Ca2+ dynamics need to be tightly regulated. Ca2+ stores are refilled through a process called store-operated Ca2+ entry (SOCE). Signaling through the store-operated Ca2+ release-activated Ca2+ (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca2+ homeostasis. Two different research teams have demonstrated that mutations in the CRAC channel pore-forming protein ORAI1 or the Ca2+ sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and slowly progressive myopathy. In the first article, the authors identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca2+-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand the understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca2+ entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.In a second article, the authors investigated three unrelated patients with tubular-aggregate myopathy and slowly progressive muscle weakness manifesting in the first years of life. All patients showed type 1 muscle fiber predominance and hypotrophy of type 2 fibers. Tubular aggregates were abundant. In all three patients, mutations were identified in the gene STIM1, and the mutations were found to be de novo in all patients. In one of the patients, the mutation was identified by exome sequencing. Two patients harbored the previously described mutation c.326A>G p.(His109Arg), while the third patient had a novel mutation c.343A>T p.(Ile115Phe). Taking this series together with previously published cases, the c.326A>G p.(His109Arg) seems to be a hotspot mutation that is characteristically related to early onset muscle weakness.
