Functional analyses of STIM1 mutations reveal a common pathomechanism for tubular aggregate myopathy and Stormorken syndrome

Abstract

Tubular aggregate myopathy (TAM) is a progressive disorder essentially involving muscle weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome (STRMK), associating TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. TAM and Stormorken syndrome arise from gain-of-function mutations in STIM1 or ORAI1, both encoding key regulators of Ca2+ homeostasis, and mutations in either gene results in excessive Ca2+ entry. The pathomechanistic similarities and differences of TAM and Stormorken syndrome are only partially understood. Here we provide functional in cellulo experiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants recruit ORAI1 to the clusters, induce major nuclear import of the Ca2+-dependent transcription factor NFAT, and trigger the formation of circular membrane stacks. In conclusion, the analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function and downstream effects of excessive Ca2+ entry, highlighting that TAM and Stormorken syndrome involve a common pathomechanism.