STIM1 – Stormorken syndrome

Stormorken syndrome is an autosomal dominant multisystem disorder characterized by tubular aggregate myopathy, bleeding diathesis, hyposplenism, miosis, ichthyosis, short stature, dyslexia and hypocalcemia. Gain-of--function mutations in the endoplasmic reticulum Ca²⁺ sensor STIM1 underlie excessive store-operated Ca²⁺ entry via ORAI1, leading to the clinical spectrum of Stormorken syndrome.

Initial genetic evidence emerged from detection of the recurrent c.910C>T (p.Arg304Trp) variant segregating with disease in six patients across four families (PMID:24619930) and review of eleven additional unrelated probands confirmed genotype–phenotype correlation with STIM1 coiled-coil domain variants (PMID:30374325).

The variant spectrum comprises missense substitutions in the luminal EF-hand (e.g., c.252T>A (p.Asp84Glu), c.325C>G (p.His109Arg)) and cytosolic coiled-coil domains (notably p.Arg304Trp and p.Arg304Gln), with recurrent founder alleles such as c.910C>T (p.Arg304Trp) in multiple European pedigrees (PMID:28624464).

Functional assays demonstrate that coiled-coil variants disrupt STIM1 autoinhibition, induce constitutive clustering at ER–PM junctions, and chronically activate ORAI1 channels. Calcium imaging in patient fibroblasts and heterologous cells shows elevated resting Ca²⁺, while zebrafish models expressing p.Arg304Trp recapitulate thrombocytopenia and muscle defects (PMID:25044882; PMID:24591628).

Structural studies including molecular modeling and FRET analyses reveal that R304W elongates the CC1 helix, increases CC1 homomerization, and exposes the CAD/SOAR domain, triggering ORAI1 recruitment without store depletion (PMID:29483506).

Rare in-frame deletions (e.g., c.702_725del) and novel EF-hand mutations expand the phenotypic spectrum to include immunological involvement and incomplete penetrance, underscoring the need for comprehensive genetic screening in patients with myopathy and hematologic abnormalities (PMID:31448844).

Key take-home: Autosomal dominant STIM1 gain-of-function variants cause Stormorken syndrome via constitutive CRAC channel activation; targeted genetic testing for hotspot mutations (e.g., c.910C>T) informs diagnosis, family counseling, and potential therapies aimed at modulating SOCE.

References

• Human mutation • 2014 • A dominant STIM1 mutation causes Stormorken syndrome. PMID:24619930
• Human mutation • 2014 • Gain-of-Function Mutation in STIM1 (P.R304W) Is Associated with Stormorken Syndrome. PMID:25044882
• Proceedings of the National Academy of Sciences of the United States of America • 2014 • Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. PMID:24591628
• Neuromuscular disorders : NMD • 2017 • Complex phenotypes associated with STIM1 mutations in both coiled coil and EF-hand domains. PMID:28624464
• Human mutation • 2020 • Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation. PMID:31448844
• Nature communications • 2018 • A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state. PMID:29483506

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