A single amino acid deletion in the ER Ca2+ sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome–causing R304W mutation

Reversing STIM1 dysfunction in Stormorken syndromeGain-of-function mutations in the ER Ca2+ sensor STIM1 result in constitutive activity of the plasma membrane Ca2+ channel Orai1 and underlie an inherited disease called Stormorken syndrome. Gamage and Grabmayr et al. found that deletion of Glu296 in STIM1 reversed the biophysical and pathophysiological effects of the most common mutation (R304W) associated with Stormorken syndrome. Mice expressing STIM1 with both the R304W mutation and Glu296 deletion were healthy and did not show the skeletal muscle, platelet, and bone phenotypes of mice expressing the R304W STIM1 mutant. Electrophysiological and biophysical analyses revealed that deletion of Glu296 in the R304W mutant restored the protein domain interactions that prevent STIM1 from associating with and activating Orai1 in the absence of stimuli. These results underscore the importance of intramolecular contacts in STIM1 in restraining its ability to stimulate Ca2+ influx through Orai1.—WW