Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome

Abstract

Stormorken syndrome is a rare autosomal dominant disorder characterized by a phenotype that includes miosis, thrombocytopenia/thrombocytopathy with bleeding time diathesis, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis. Using targeted sequencing and whole-exome sequencing, we identified the c.910C > T transition in a STIM1 allele (p.R304W) only in patients and not in their unaffected family members. STIM1 encodes stromal interaction molecule 1 protein (STIM1), which is a finely tuned endoplasmic reticulum Ca 2+ sensor. The effect of the mutation on the structure of STIM1 was investigated by molecular modeling, and its effect on function was explored by calcium imaging experiments. Results obtained from calcium imaging experiments using transfected cells together with fibroblasts from one patient are in agreement with impairment of calcium homeostasis. We show that the STIM1 p.R304W variant may affect the conformation of the inhibitory helix and unlock the inhibitory state of STIM1. The p.R304W mutation causes a gain of function effect associated with an increase in both resting Ca 2+ levels and store-operated calcium entry. Our study provides evidence that Stormorken syndrome may result from a single-gene defect, which is consistent with Mendelian-dominant inheritance.

Stormorken syndrome or York platelet syndrome: A clinician's dilemma

“…Analysis of our observations [2] together with a review of other cases [3], [4] suggests that patients with the c.910C>T mutation in STIM1 gene (p.R304W) have the same heterogeneous disease and that Stormorken syndrome (StS) and York platelet syndrome (YPS) are probably two different names for the same clinical condition. The confusion could be due to the strategy used to study platelets.…”

“…Indeed, in patients affected with YPS platelets have been extensively studied by electron microscopy, not in the patients with StS. It should be noted that among the many biological symptoms of StS, thrombocytopenia and thrombocytopathia have been first described as major and constant defects [2], [3], [4], [5].…”

Calcium Dyshomeostasis in Tubular Aggregate Myopathy

“…Store-operated Ca 2+ entry induced by thapsigargin treatment was moderately increased in HEK293 cells transfected with this mutant [64,85,90]. These cells have shown the presence of STIM1 puncta in both thapsigargin-treated and untreated cells [65,66,85,91]. Thus, these data indicate that the Arg304Trp mutation results in constitutive Ca 2+ influx.…”

“…Thrombocytopenia or thrombocytopathia is frequently observed in most patients with a bleeding tendency [64,84,85]. So far, patients with the STIM1 Arg304Trp mutation reported by Misceo et al have shown hematoma after minor trauma, recurrent epistaxis, subarachnoid hemorrhage, and skin purpura [84].…”

“…This mutation is located in the CC1 domain and results in constitutive Ca 2+ influx without SR/ER Ca 2+ depletion [64,84,85,89]. Store-operated Ca 2+ entry induced by thapsigargin treatment was moderately increased in HEK293 cells transfected with this mutant [64,85,90]. These cells have shown the presence of STIM1 puncta in both thapsigargin-treated and untreated cells [65,66,85,91].…”