A luminal EF-hand mutation in STIM1 in mice causes the clinical hallmarks of tubular aggregate myopathy

Abstract

STIM and ORAI proteins play a fundamental role in calcium signalling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores in a process known as Store Operated Ca2+ Entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In the present contribution, we describe the generation and characterization of a knock-in mouse model (KI-STIM1I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased Store Operated Ca2+ Entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant creatine kinase increase. Yet, animals have a significantly worst performance in the rotarod and treadmill tests, showing an increased susceptibility to fatigue, in analogy to the human disease. The mice also show an increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with the recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions.