Bleeding tendency is a major part of Stormorken syndrome (OMIM 185070), and repeated bleeding in a young boy was how the first patient came to Professor Helge Stormorken’s attention in 1974. Patients with Stormorken syndrome exhibit mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, splenic aplasia/functional asplenia, tubular aggregate myopathy, and miosis (Stormorken et al., 1985; Stormorken, 2002).
We documented that the missense mutation STIM1 p.R304W causes the autosomal dominant Stormorken syndrome (Misceo et al., 2014). In a parallel study the same mutation was identified in two independent patients (Nesin et al., 2014), and later additional patients were described (Morin et al., 2014).
STIM1 is an ER membrane protein that initiates store-operated Ca2+ entry (SOCE) into the cell when ER Ca2+ levels are low. When activated, STIM1 interacts with ORAI1, which is a Ca2+ channel on the plasma membrane that enables Ca2+ influx into the cytoplasm. The STIM1 R304W mutation destabilizes the conformation of STIM1 in resting state leading to constitutive Ca2+influx into the cell (Fahrner et al., 2018).
Following our finding we established a knock-in model expressing STIM1 R304W in F1 (c57bl/6xCBA) mice using the CompoZrTMZFN design. STIM1 R304W was lethal in the homozygous state, however, the few surviving mice presented with skeletal muscle degeneration (Figure; Gamage et al., 2018). The mice also presented with increased bone volume as well as subgingival hair growth on the lower incisors (Figure; Gamage and Lengle et al., 2020).
Our findings highlight the importance of STIM1 in the development and homeostasis of the skeleton and the skeletal muscle. STIM1 R304W in mice also seems to induce an abnormal epithelial cell fate.
Prof. G. Gunnes (NMBU): Pathology and histology
Dr. W. Louch and Prof. G. Christiansen (OUS): Ca2+ influx analyses
Profs. P.A. Holme and G. Tjønnfjord (OUS): Hematology
Prof. S.P. Lyngstadaas (UiO): Analysis of bone structure
Prof. W. Bergmeier (University of North Carolina at Chapel Hill, USA): Mouse platelet biology
Prof. R. Lacruz (Sackler Institute, NYU School of Medicine, USA): Tooth development
Prof. C. Romanin (Johannes Kepler University Linz, Austria): STIM1 conformational changes
Examples from this work: