A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state

Fahrner, Marc; Stadlbauer, Michael; Muik, Martin; Rathner, Petr; Stathopulos, Peter B.; Ikura, Mitsu; Müller, Norbert; Romanin, Christoph

doi:10.1038/s41467-018-03062-w

Cited by 46 publications

(85 citation statements)

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“…The substitution of R304 by tryptophan (p.R304W), and to lesser extent by glutamine (p.R304Q), increases the local hydrophobicity and α‐helical rigidity, and leads to the conformational change of the second and third CC1 α‐helix. This compromises the maintenance of the CC1–CC3 clamp, ultimately destabilizes the tight conformation of STIM1, promotes the exposure of the SOAR domain, and enhances the CC1–CC1 homodimerization and the activation of ORAI1 independently of the reticular Ca 2+ load (Fahrner et al, ).…”

Section: Stim1 and Orai1 Mutationsmentioning

confidence: 99%

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

et al. 2019

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Calcium (Ca2+) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca2+ entry, storage, and release. Store‐operated Ca2+ entry (SOCE) is a major mechanism controlling extracellular Ca2+ entry, and mainly relies on the accurate interplay between the Ca2+ sensor STIM1 and the Ca2+ channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca2+ homeostasis and are associated with severe human disorders. Recessive loss‐of‐function mutations impair SOCE and cause combined immunodeficiency, while dominant gain‐of‐function mutations induce excessive extracellular Ca2+ entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.

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Section: Stim1 and Orai1 Mutationsmentioning

confidence: 99%

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

et al. 2019

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“…Briefly, mutations of STIM1 mostly reside in the EF-hand Ca 2+ -binding motifs, most likely modifying the affinity for Ca 2+ ions of the protein, with few exceptions located on the cytosolic coiled-coil domains. The R304W mutation has recently been shown to affect the dimerization and resting state of STIM1 (Fahrner et al, 2018). A second substitution at the same position (R304Q; Harris et al, 2015) and a deletion on the third coiled-coil domain have also been reported (I484R fs*21; Okuma et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A luminal EF-hand mutation in STIM1 in mice causes the clinical hallmarks of tubular aggregate myopathy

Cordero-Sánchez

Riva

Reano

et al. 2019

Disease Models &Amp; Mechanisms

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STIM and ORAI proteins play a fundamental role in calcium signaling, allowing for calcium influx through the plasma membrane upon depletion of intracellular stores, in a process known as store-operated Ca 2+ entry. Point mutations that lead to gain-of-function activity of either STIM1 or ORAI1 are responsible for a cluster of ultra-rare syndromes characterized by motor disturbances and platelet dysfunction. The prevalence of these disorders is at present unknown. In this study, we describe the generation and characterization of a knock-in mouse model (KI-STIM1 I115F) that bears a clinically relevant mutation located in one of the two calcium-sensing EF-hand motifs of STIM1. The mouse colony is viable and fertile. Myotubes from these mice show an increased store-operated Ca 2+ entry, as predicted. This most likely causes the dystrophic muscle phenotype observed, which worsens with age. Such histological features are not accompanied by a significant increase in creatine kinase. However, animals have significantly worse performance in rotarod and treadmill tests, showing increased susceptibility to fatigue, in analogy to the human disease. The mice also show increased bleeding time and thrombocytopenia, as well as an unexpected defect in the myeloid lineage and in natural killer cells. The present model, together with recently described models bearing the R304W mutation (located on the coiled-coil domain in the cytosolic side of STIM1), represents an ideal platform to characterize the disorder and test therapeutic strategies for patients with STIM1 mutations, currently without therapeutic solutions.

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“…The luminal R304W mutation does not interfere with Ca 2+ binding. Instead, a recent study revealed that it induces a helical elongation within the coiled-coil domain, and thereby promotes STIM1 clustering and the exposure of the SOAR domain (37). In both cases, the mutations induce constitutive ORAI1 binding and activation, resulting in major extracellular Ca 2+ influx despite replete Ca 2+ stores (4, 10–12).…”

Section: Discussionmentioning

confidence: 99%

Functional analyses ofSTIM1mutations reveal a common pathomechanism for tubular aggregate myopathy and Stormorken syndrome

Peche

Spiegelhalter

Silva-Rojas

et al. 2019

Preprint

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22Tubular aggregate myopathy (TAM) is a progressive disorder essentially involving muscle 23 weakness, cramps, and myalgia. TAM clinically overlaps with Stormorken syndrome 24 (STRMK), associating TAM with miosis, thrombocytopenia, hyposplenism, ichthyosis, short 25 stature, and dyslexia. TAM and Stormorken syndrome arise from gain-of-function mutations in 26 STIM1 or ORAI1, both encoding key regulators of Ca 2+ homeostasis, and mutations in either 27 gene results in excessive Ca 2+ entry. The pathomechanistic similarities and differences of TAM 28 and Stormorken syndrome are only partially understood. Here we provide functional in cellulo 29 experiments demonstrating that STIM1 harboring the TAM D84G or the STRMK R304W 30 mutation similarly cluster and exert a dominant effect on the wild-type protein. Both mutants 31 recruit ORAI1 to the clusters, induce major nuclear import of the Ca 2+ -dependent transcription 32 factor NFAT, and trigger the formation of circular membrane stacks. In conclusion, the 33 analyzed TAM and STRMK mutations have a comparable impact on STIM1 protein function 34 and downstream effects of excessive Ca 2+ entry, highlighting that TAM and Stormorken 35 syndrome involve a common pathomechanism. 36 37 Keywords: STIM1, tubular aggregate myopathy, Stormorken syndrome, SOCE, calcium 38 39 40 41 42 Functional analysis of STIM1 mutations 3 43 44 Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are spectra of the 45 same disease affecting muscle, platelets, spleen, and skin (1, 2). The majority of the TAM 46 patients primarily present with muscle weakness, cramps, and myalgia with a heterogeneous 47 age of onset and disease severity (3-6). Additional features including thrombocytopenia, 48 hyposplenism, miosis, ichthyosis, short stature, hypocalcemia, or dyslexia can be seen as well, 49 and the occurrence of the totality of the multi-systemic signs constitutes the diagnosis of 50Stormorken syndrome (7-18). 51Both TAM and Stormorken syndrome are characterized by the presence of densely packed 52 membrane tubules in muscle fibers, and investigations on muscle sections by 53 immunofluorescence have shown that these tubular aggregates contain various sarcoplasmic 54 reticulum (SR) proteins, suggesting that they originate from the SR (4, 7, 15, 16, 19). The 55 tubular aggregates are the histopathological hallmark of TAM and Stormorken syndrome, and 56 were also described in hypokalemic periodic paralysis, myasthenic syndrome, malignant 57 hyperthermia, inflammatory or ethyltoxic myopathy, and accumulate in normal muscle with 58 age (20-25). 59TAM and Stormorken syndrome are caused by heterozygous missense mutations in STIM1 (4, 60 10-12) (OMIM #605921) or ORAI1 (12) (OMIM #610277), both encoding key factors of store-61 operated Ca 2+ entry (SOCE). SOCE is a major mechanism regulating Ca 2+ homeostasis and 62 thereby drives a multitude of Ca 2+ -dependent cellular functions including muscle contraction. 63STIM1 has a single transmembrane domain and is primarily localized at the 64 endo...

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A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state

Cited by 46 publications

References 44 publications

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation

A luminal EF-hand mutation in STIM1 in mice causes the clinical hallmarks of tubular aggregate myopathy

Functional analyses ofSTIM1mutations reveal a common pathomechanism for tubular aggregate myopathy and Stormorken syndrome

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