ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome

• DOI: 10.1172/jci.insight.174866
• Publication Date: 2024-04-05T12:26:26Z
• Authors: Roberto Silva-Rojas; Laura Pérez-Guàrdia; Alix Simon; Sarah Djeddi; Susan Treves; Agnès Ribes; Lorenzo Silva-Her...; Céline Tard; Jocelyn Laporte; Johann Böhm
• Keywords: Orai1; Haploinsufficiency; Noonan Syndrome

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, hyposplenism. TAM/STRMK is caused gain-of-function mutations in the Ca2+ sensor STIM1 or channel ORAI1, both which regulate homeostasis through ubiquitous store-operated entry (SOCE) mechanism. Functional experiments cells have demonstrated that induce SOCE overactivation, resulting excessive influx extracellular Ca2+. There currently no treatment for TAM/STRMK, but amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring most common mutation with Orai1R93W/+ carrying an ORAI1 partially obstructing influx. Compared littermates, Stim1R304W/+Orai1R93W/+ offspring showed normalization bone architecture, spleen histology, morphology; increase thrombocytes; improved contraction relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes revealed major restoration gene expression mice. Altogether, provide physiological, morphological, functional, molecular data highlighting therapeutic potential inhibition rescue identified myostatin as promising biomarker humans