Tubular aggregate myopathy with features of Stormorken disease due to a new STIM1 mutation

Noury, Jean-Baptiste; Böhm, Johann; Peche, Georges Arielle; Guyant‐Maréchal, Lucie; Bédat-Millet, Anne-Laure; Chiche, Léa; Carlier, Robert‐Yves; Malfatti, Edoardo; Romero, Norma B.; Stojkovic, Tanya

doi:10.1016/j.nmd.2016.10.006

Cited by 41 publications

(56 citation statements)

References 15 publications

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“…A mutation in STIM1 (D84E) resulting in TAM and Stormorken syndrome, also reported “tooth enamel hypocalcification”. Beyond this limited dental description, no other data on enamel were reported [47]. The patient showed hypocalcemia in laboratory tests which directly or indirectly affected the mineralization of the enamel as hypocalcemia in general impacts enamel [48].…”

Section: Enamel Defects In Patients With Loss-of-function Mutation Inmentioning

confidence: 99%

CRAC channels in dental enamel cells

Eckstein

Lacruz

2018

Cell Calcium

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Enamel mineralization relies on Ca availability provided by Ca release activated Ca (CRAC) channels. CRAC channels are modulated by the endoplasmic reticulum Ca sensor STIM1 which gates the pore subunit of the channel known as ORAI1, found the in plasma membrane, to enable sustained Ca influx. Mutations in the STIM1 and ORAI1 genes result in CRAC channelopathy, an ensemble of diseases including immunodeficiency, muscular hypotonia, ectodermal dysplasia with defects in sweat gland function and abnormal enamel mineralization similar to amelogenesis imperfecta (AI). In some reports, the chief medical complain has been the patient's dental health, highlighting the direct and important link between CRAC channels and enamel. The reported enamel defects are apparent in both the deciduous and in permanent teeth and often require extensive dental treatment to provide the patient with a functional dentition. Among the dental phenotypes observed in the patients, discoloration, increased wear, hypoplasias (thinning of enamel) and chipping has been reported. These findings are not universal in all patients. Here we review the mutations in STIM1 and ORAI1 causing AI-like phenotype, and evaluate the enamel defects in CRAC channel deficient mice. We also provide a brief overview of the role of CRAC channels in other mineralizing systems such as dentine and bone.

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Section: Enamel Defects In Patients With Loss-of-function Mutation Inmentioning

confidence: 99%

CRAC channels in dental enamel cells

Eckstein

Lacruz

2018

Cell Calcium

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“…E152K is located in the EF-SAM domain, a region previously identified as being crucial for STIM1 function. So far, the role of the STIM1 EF-SAM domain has been uniquely associated with SOCE activation (Stathopulos et al, 2006;Stathopulos et al, 2008) whereas gain of function mutations in the EF-hand domain have only been associated with the constitutive activation of STIM1 and SOCE (Böhm et al, 2013;Lacruz and Feske, 2015;Noury et al, 2017). Here, we reveal a gain of function for the STIM1-E152K variant potentially caused by altered interactions with SERCA rather than enhanced EF-SAM oligomerization.…”

Section: Discussionmentioning

confidence: 67%

“…The association between STIM1 gene variants and the development of different diseases has been elucidated. Among them, we can find STIM1 variants driving to loss of function in autoimmunity and immunodeficiencies like E136X (Picard et al, 2009) and homozygous p.L74P and p.L374P (Parry et al, 2016;Vaeth et al, 2017), or reporting a gain of function like p.D84G/p.H84N/p.H109R for tubular-aggregate myopathy (Böhm et al, 2013), p.R304W for Stormorken syndrome (Misceo et al, 2014;Morin et al, 2014;Nesin et al, 2014), p.I115F (Hedberg et al, 2014) and p.D84E (Noury et al, 2017) for tubular-aggregate myopathy, and p.S88G/p.R304Q for neuromuscular malfunctions (Harris et al, 2017). The importance of Ca 2+ signaling for the regulation of pancreatic zymogen activation and the key role of STIM1 in this process suggests that variants in the STIM1 gene may also contribute to chronic pancreatitis by disturbing Ca 2+ homeostasis within the pancreatic tissue.…”

Section: Introductionmentioning

confidence: 99%

p.E152K-STIM1 mutation deregulates Ca²⁺signaling contributing to chronic pancreatitis

Burgos

Philippe

Antigny

et al. 2020

Preprint

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statement: p.E152K-STIM1 variant found in pancreatitis patients leads to intracellular changes in calcium homeostasis through SERCA interaction, enabling intracellular trypsin activation and pancreatic acinar cell death. ABSTRACTSince deregulation of intracellular Ca 2+ can lead to intracellular trypsin activation and STIM1 (stromal interaction molecule-1) protein is the main regulator of Ca 2+ homeostasis in pancreatic acinar cells, we explored the Ca 2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca 2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca 2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1-sarco/endoplasmic reticulum calcium transport ATPase (SERCA) interactions and enhanced SERCA pump activity leading to increased Store Operated Calcium Entry (SOCE).In the pancreatic AR42J cells expressing the p.E152K variant, Ca 2+ -signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.

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“…Tubular aggregate myopathy essentially affects skeletal muscle, and a subset of TAM patients harboring STIM1 EF-hand mutations additionally manifested one or several signs of Stormorken syndrome (3–5, 8, 9, 18). Conversely, Stormorken syndrome patients carrying the most common R304W mutation usually present the full clinical picture of TAM, miosis, thrombocytopenia, hyposplenism, ichthyosis, short stature, and dyslexia (7, 10–14), but individual patients with muscle weakness as the main clinical sign were also reported (9).…”

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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Tubular aggregate myopathy with features of Stormorken disease due to a new STIM1 mutation

Cited by 41 publications

References 15 publications

CRAC channels in dental enamel cells

CRAC channels in dental enamel cells

p.E152K-STIM1 mutation deregulates Ca²⁺signaling contributing to chronic pancreatitis

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

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Tubular aggregate myopathy with features of Stormorken disease due to a new STIM1 mutation

Cited by 41 publications

References 15 publications

CRAC channels in dental enamel cells

CRAC channels in dental enamel cells

p.E152K-STIM1 mutation deregulates Ca2+signaling contributing to chronic pancreatitis

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

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p.E152K-STIM1 mutation deregulates Ca²⁺signaling contributing to chronic pancreatitis