DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Stormorken syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleStormorken syndrome maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for stormorken syndrome is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
stromal interaction molecule 1 (STIM1) — STIM1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4O9B · 2.604 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Stormorken syndrome is a rare autosomal dominant disorder caused by gain-of-function mutations in the STIM1 gene, which encodes an endoplasmic reticulum calcium sensor. The most frequently reported mutation is p.R304W, a c.910C>T transition in STIM1 that produces a constitutively active protein by destabilising the inhibitory interaction between the coiled-coil 1 (CC1) and CC3 domains, leading to increased resting calcium levels and constitutive CRAC channel activation. A 2014 study identified this mutation in affected family members only, and calcium imaging in transfected cells and patient fibroblasts confirmed impaired calcium homeostasis. A 2018 review of 11 reported patients and 50 STIM1 mutations suggested a genotype-phenotype correlation: mutations in the coiled-coil cytoplasmic domain were associated with complete Stormorken syndrome, while variants outside this region more often produced an incomplete phenotype. A 2022 case report described a child with a different mutation, p.H109R (c.326A>G), found de novo in the child but not in unaffected parents; STIM1 protein levels were not decreased. That review tallied 46 cases across 30 families with EF-hand mutations, 21 cases across 14 families with CC1 mutations, and 20 cases across 8 families with ORAI1 mutations.
The 2023 study found that adding a single amino acid deletion, E296del, in cis with the R304W mutation reversed the pathological effects in cellular experiments and in mice. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spectroscopy and molecular dynamics simulations showed that E296del restored CC1-CC3 binding, opposing the R304W-induced constitutive activation. This work clarifies the molecular basis of STIM1 activation and the pathophysiology of the R304W mutation, but it is a preclinical mechanistic study, not a therapeutic trial.
No drug treatment for Stormorken syndrome is mentioned in any of these abstracts. The 2022 case report noted that long-term exercise training may have a certain curative effect, but provided no data on outcomes. What remains missing is any clinical trial testing a pharmacological intervention, any patient stratification beyond genotype, and any funding directed toward drug development for this extremely rare disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Mutation · 2014 · 114 citations
Gain‐of‐Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome
AbstractStormorken 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.
Frontiers in Neurology · 2018 · 30 citations · open access
Stormorken Syndrome Caused by a p.R304W STIM1 Mutation: The First Italian Patient and a Review of the Literature
AbstractStormorken syndrome is a rare autosomal dominant disorder characterized by a complex phenotype including tubular aggregate myopathy (TAM), bleeding diathesis, hyposplenism, mild hypocalcemia and additional features such as miosis and mild intellectual disability (dyslexia). Stormorken syndrome is caused by autosomal dominant mutations in the STIM1 gene, which encodes an endoplasmic reticulum Ca2+ sensor. Here, we present the clinical and molecular features of a 21-year-old Italian female with Stormorken syndrome. The STIM1 gene sequence identified a c.910C > T transition in a STIM1 allele (p.R304W). The p.R304W mutation is a common mutation that is responsible for Stormorken syndrome and is hypothesized to cause a gain of function effect associated with an increase in Ca2+. A review of published STIM1 mutations (n = 50) and reported Stormorken patients (n = 11) suggested a genotype-phenotype correlation with mutations in a coiled-coil cytoplasmic domain associated with complete Stormorken syndrome, while other pathological variants outside this region were more often linked to an incomplete phenotype. Our study describes the first Italian patient with Stormorken syndrome, contributes to the genotype/phenotype correlation and highlights the possibility of directly investigating the p.R304W mutation in the presence of a typical phenotype.
Medicine International · 2022 · 3 citations · open access
Stormorken syndrome caused by <i>STIM1</i> mutation: A case report and literature review
AbstractThe aim of the present case study was to identify the genetic cause of a patient with a clinical presentation of tubular aggregate myopathy (TAM)/Stormorken syndrome (STRMK) and review the published clinical data of patients with TAM/STRMK. A child with thrombocytopenia and hyperCKemia at the Children's Hospital of Soochow University were recruited in the study. Peripheral blood samples of the infant and her parents were collected, and then whole‑exome sequencing was performed. Detection of the stromal interaction molecule 1 (STIM1) level of the child was performed using western blot analysis. In addition, a literature review was performed based on a thorough retrieval of published literature from the PubMed database, as well as domestic databases. In the present study, the c.326A>G mutation in a <em>STIM1</em> allele (p.H109R) was identified only in the child, as opposed to the unaffected parents. The level of STIM1 was not decreased in the child. Among the mutation sites identified in previous studies, there were 46 cases across 30 families of <em>STIM1</em> EF‑hand mutations, 21 cases across 14 families of <em>STIM1</em> CC1 mutations and 20 cases across 8 families of calcium release‑activated calcium channel protein 1 mutations, in which 7 parents had the same mutation site as the patient described herein. On the whole, it is demonstrated that TAM/STRMK is an extremely rare disease with autosomal dominant inheritance. Patients often have multisystemic signs. Gene detection at an early stage is helpful for diagnosis. Long‑term exercise training may also have a certain curative effect.
Zenodo (CERN European Organization for Nuclear Research) · 2023 · 0 citations · open access
A single amino acid deletion in the ER Ca2+ sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation
AbstractStormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular "clamp" formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spectroscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W mutation prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.
Zenodo (CERN European Organization for Nuclear Research) · 2023 · 0 citations · open access
A single amino acid deletion in the ER Ca2+ sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation
AbstractStormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular "clamp" formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spectroscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W mutation prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.
Data Archiving and Networked Services (DANS) · 2022 · 0 citations · open access
Stormorken Syndrome Caused by STIM1 H109R Mutation
AbstractStormorken Syndrome is an extremely rare disease with autosomal dominant inheritance, has a variable degree of multisystemic signs, including muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia. we identified the c.326A>G mutation in a STIM1 allele (p.H109R) only in the child and not in the unaffected parents. The mutation was predicted to be harmful by protein function prediction software. We found mutations associated with TAM/STRMK upon consulting HGMD database. The variant located in the EF-hand supposedly led to constitutive STIM1 unfolding and oligomerization. The affected amino acids in this residue was evolutionarily conserved, which indicated an important functional role. The 3D structures of STIM1 and mutated proteins were constructed in SWISS-MODEL. No differences in STIM1 expression levels were observed between our case and healthy controls.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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