Public Defence: Y. G. Thilini Hansamali Gamage

MSc Y.G. Thilini Hansamali Gamage at Institute of Clinical Medicine will be defending the thesis “Characterization of the effect of Stim1 mutations using knock-in mouse models” for the degree of PhD (Philosophiae Doctor).

Trial Lecture – time and place

See Trial Lecture.

Adjudication committee

  • First opponent: Professor Shmuel Muallem, National Institute of Dental and Craniofacial Research, NIH, USA
  • Second opponent: Professor Harald Carlsen, Faculty of Chemistry, Norwegian University of Life Sciences
  • Third member and chair of the evaluation committee: Senior Researcher Cathrine Rein Carlson, Faculty of Medicine, University of Oslo

Chair of the Defence

Associate Professor Ingrid Randen, Faculty of Medicine, University of Oslo

Principal Supervisor

Principal Supervisor Eirik Frengen, Faculty of Medicine, University of Oslo


In 1985, Professor Helge Stormorken described a novel syndrome, Stormorken syndrome, characterized by muscle and hematological defects, miosis, asplenia, and ichthyosis. Nearly 30 years later we identified an amino acid substitution in the Stromal interacting molecule 1 (STIM1) as the cause of this genetic disease.

STIM1 is located on the endoplasmic reticulum (ER) sensing the Ca2+ levels in the ER lumen- the main Ca2+ storage in most cells. At low ER Ca2+ levels, STIM1 is activated and interacts with a plasma membrane Ca2+ channel facilitating Ca2+ influx to the cell, a process named store operated Ca2+ entry (SOCE). In patient cells, the mutant STIM1 R304W is constitutively activated causing increased Ca2+ influx. This thesis aimed to characterize the biological effects of the mutant protein by establishing a mouse model expressing STIM1 R304W.

Characterization of the Stim1R304W mice showed that most homozygous animals died at birth, while the few surviving mice showed reduced growth, reduced exercise endurance and severe skeletal muscle degeneration. The STIM1 R304W protein also showed reduced expression in platelets and megakaryocytes leading to impaired platelet activation. We further documented impaired bone architecture, reduced bone marrow cavity and ectopic sub-gingival hair growth in Stim1R304W mice. Disease severity increased from heterozygous to homozygous mice.

A second mouse model, Stim1ΔKI, expressing a double mutant Stim1 allele showed a rescue of the phenotype seen in the Stim1R304W mice. In vitro expression of the Stim1ΔKI allele showed that the double mutant Stim1 allele lead the protein to readapt almost fully the folded quiescent conformation in the resting state.

In summary, our results highlight the importance of a tight regulation of Ca2+ flux during bone, dental and muscle development. In addition, the results revealed detailed knowledge about structural changes causing constitutively activated STIM1 R304W.

Additional information

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Published Dec. 4, 2019 1:26 PM - Last modified Dec. 5, 2019 12:03 PM