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.
Stormorken syndrome patients exhibit mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, splenic aplasia/functional asplenia, tubular aggregate myopathy, and miosis (Stormorken et al., 1985; Stormorken, 2002).
By whole exome sequencing (WES) in a family trio and one unrelated patient 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 (Nesinet 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) 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 has been shown to destabilize 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 reduced growth and skeletal muscle degeneration (Gamage et al., 2018). Our data highlight the importance of STIM1 in skeletal muscle development and integrity.
Prof. G. Gunnes (NMBU): Pathology and histology
Dr. W. Louch and Prof. G. Christiansen (OUS): Analysis of Ca2+influx
Profs. P.A. Holme and G. Tjønnfjord (OUS): Hematology
Prof. A. Klungland (OUS): Mouse models
Prof. W. Bergmeier (University of North Carolina at Chapel Hill, USA): Mouse platelet biology
Prof. H. Westerblad (Karolinska Institute, Sweden): Muscle physiology
Prof. C. Romanin (Johannes Kepler University Linz, Austria): STIM1 conformational changes
Publications from the group