Stormorken syndrome is a rare genetic disorder (MIM 185070) first reported in 1983 with thrombocytopenia, muscle weakness, asplenia, and miosis caused by a mutation of the stromal interaction molecule 1 ( STIM1) gene. The muscle weakness is caused by a myopathy with tubular aggregate formation. We report a family in which both child and mother presented with proximal muscle weakness and thrombocytopenia. Histologic, histochemical, and electron microscopy studies were performed on the muscle specimen. It documented accumulation of tubular aggregates and chronic myopathic changes with dystrophic features. Genetic testing revealed that both mother and son carried a missense mutation of c.326A>G in exon 3 of the STIM1 gene, which is novel for Stormorken syndrome. We suggest that patients with unexplained chronic idiopathic thrombocytopenia and proximal weakness have genetic testing for Stormorken syndrome.
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A Gain-of-Function Mutation in the Ca Channel ORAI1 Causes Stormorken Syndrome with Tubular Aggregates in Mice.
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November 2024
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France.
Store-operated Ca entry (SOCE) controls Ca homeostasis and mediates multiple Ca-dependent signaling pathways and cellular processes. It relies on the concerted activity of the reticular Ca sensor STIM1 and the plasma membrane Ca channel ORAI1. STIM1 and ORAI1 gain-of-function (GoF) mutations induce SOCE overactivity and excessive Ca influx, leading to tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK), two overlapping disorders characterized by muscle weakness and a variable occurrence of multi-systemic anomalies affecting spleen, skin, and platelets.
View Article and Find Full Text PDFORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome.
JCI Insight
March 2024
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR7104, University of Strasbourg, Illkirch, France.
Article Synopsis
- * Experimental mouse models showed that pairing a TAM mutation (Stim1R304W) with a partial ORAI1 mutation (Orai1R93W) led to positive health outcomes, including improved bone structure, spleen health, muscle function, and increased platelet counts.
- * The study suggests that targeting ORAI1 could offer a potential treatment strategy for TAM/STRMK, and identified myostatin as a potential biom
ORAI Calcium Channels: Regulation, Function, Pharmacology, and Therapeutic Targets.
Pharmaceuticals (Basel)
January 2023
Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institute and Karolinska University Hospital, C1:68, 141 86 Stockholm, Sweden.
The changes in intracellular free calcium (Ca) levels are one of the most widely regulators of cell function; therefore, calcium as a universal intracellular mediator is involved in very important human diseases and disorders. In many cells, Ca inflow is mediated by store-operated calcium channels, and it is recognized that the store-operated calcium entry (SOCE) is mediated by the two partners: the pore-forming proteins Orai (Orai1-3) and the calcium store sensor, stromal interaction molecule (STIM1-2). Importantly, the Orai/STIM channels are involved in crucial cell signalling processes such as growth factors, neurotransmitters, and cytokines via interaction with protein tyrosine kinase coupled receptors and G protein-coupled receptors.
View Article and Find Full Text PDFA single amino acid deletion in the ER Ca sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation.
Sci Signal
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Department of Medical Genetics, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway.
Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca sensor protein STIM1, which forms the Ca release-activated Ca (CRAC) channel together with the plasma membrane channel Orai1. ER Ca 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 Ca store depletion, causing constitutive binding to Orai1 and CRAC channel activation.
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