A dominant STIM1 mutation causes Stormorken syndrome

Hum Mutat. 2014 May;35(5):556-64. doi: 10.1002/humu.22544. Epub 2014 Apr 9.


Stormorken syndrome is a rare autosomal-dominant disease with mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. A heterozygous missense mutation in STIM1 exon 7 (c.910C>T; p.Arg304Trp) (NM_003156.3) was found to segregate with the disease in six Stormorken syndrome patients in four families. Upon sensing Ca(2+) depletion in the endoplasmic reticulum lumen, STIM1 undergoes a conformational change enabling it to interact with and open ORAI1, a Ca(2+) release-activated Ca(2+) channel located in the plasma membrane. The STIM1 mutation found in Stormorken syndrome patients is located in the coiled-coil 1 domain, which might play a role in keeping STIM1 inactive. In agreement with a possible gain-of-function mutation in STIM1, blood platelets from patients were in a preactivated state with high exposure of aminophospholipids on the outer surface of the plasma membrane. Resting Ca(2+) levels were elevated in platelets from the patients compared with controls, and store-operated Ca(2+) entry was markedly attenuated, further supporting constitutive activity of STIM1 and ORAI1. Thus, our data are compatible with a near-maximal activation of STIM1 in Stormorken syndrome patients. We conclude that the heterozygous mutation c.910C>T causes the complex phenotype that defines this syndrome.

Keywords: CRAC; SOCE; STIM1; Stormorken syndrome; whole-exome sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood Platelet Disorders / genetics*
  • Blood Platelet Disorders / pathology
  • Calcium Channels / genetics
  • Comparative Genomic Hybridization
  • Dyslexia / genetics*
  • Dyslexia / pathology
  • Erythrocytes, Abnormal / pathology
  • Exome / genetics*
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Ichthyosis / genetics*
  • Ichthyosis / pathology
  • Male
  • Membrane Proteins / genetics*
  • Migraine Disorders / genetics*
  • Migraine Disorders / pathology
  • Miosis / genetics*
  • Miosis / pathology
  • Muscle Fatigue / genetics
  • Mutation, Missense / genetics*
  • Neoplasm Proteins / genetics*
  • ORAI1 Protein
  • Pedigree
  • Spleen / abnormalities*
  • Spleen / pathology
  • Stromal Interaction Molecule 1


  • Calcium Channels
  • Membrane Proteins
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • STIM1 protein, human
  • Stromal Interaction Molecule 1

Supplementary concepts

  • Stormorken Syndrome