STIM1 in-frame deletion of eight amino acids in a patient with moderate tubular aggregate myopathy/Stormorken syndrome

Store-operated Ca²⁺ entry (SOCE) is a ubiquitous mechanism controlling Ca²⁺ homeostasis and relies on the reticular Ca²⁺ sensor STIM1 and the plasma membrane Ca²⁺ channel ORAI1. <i>STIM1</i> and <i>ORAI1</i> gain-of-function mutations induce excessive Ca²⁺ influx through SOCE overactivation and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterised by muscle weakness and additional signs such as short stature, thrombocytopenia and hyposplenism. Most patients carry missense mutations in the STIM1 Ca²⁺-sensing EF-hands or in the CC1 domain implicated in ORAI1 activation.Here we report the first STIM1 deletion in a patient with moderate TAM/STRMK phenotype encompassing exercise-induced muscle weakness, elevated creatine kinase levels, asplenia and transient thrombocytopenia. The c.702_725del mutation occurred de novo and is predicted to involve the deletion of eight amino acids between EF-hands and the CC1 domain. We conducted a series of functional experiments in mouse and human cells lines and provided the evidence that the in-frame deletion causes constitutive STIM1 clustering and ORAI1 recruitment, resulting in profuse extracellular Ca²⁺ entry and major nuclear translocation of the transcription factor NFAT1. Overall, this work illustrated the pathogenicity of the STIM1 in-frame deletion at different levels of the SOCE pathway and provided a molecular diagnosis for the affected family.