Submission Details

ORAI1 was first reported in relation to autosomal dominant tubular aggregate myopathy in 2014 (Nesin et al., PMID: 24591628). Variants in this gene have also been reported in association with an Immunodeficiency phenotype, which will be assessed separately. At least 6 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 8 probands in 4 publications (PMIDs: 24591628, 25227914, 27882542, 28058752). Variants in this gene segregated with disease in a significant number of additional family members via whole exome sequencing. A significant amount of variant-level evidence was available, with each individual variant demonstrating altered SOCE activation and Ca2+ homeostasis. The mechanism for disease is heterozygous gain of function, with alteration of several domains responsible for altered calcium signalling detection and resulting consitutive activation of store-operated calcium entry regardless of the intracellular calcium levels. (Morin et al. 2019, PMID: 31448844) This gene-disease association and mechanism is supported by biochemical function evidence, expression evidence, physical interaction with STIM1, and functional studies demonstrating SOCE loss and rescue via ORAI1 expression. ORAI1's role in SOCE, relationship with STIM1, and the resulting always activated state when the expression and function of the protein is altered show clear correlations with the displayed phenotypes as skeletal muscle signalling relies on calcium flow. Currently there are no available models that properly demonstrate TAM phenotypes, likely due to the necessity of a knock-in model and less research performed than on STIM1. In summary, ORAI1 is definitively associated with autosomal dominant tubular aggregate myopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.