A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

Holmes, Tim D.; Gamper, Nikita; El‐Sayed, Walid; Hettiarachchi, Nishani T.; Ahmed, Mushtaq; Cook, Graham P.; Logan, Clare V.; Johnson, Colin A.; Joss, Shelagh; Peers, Chris; Prescott, Katrina; Savic, Sinisa; Inglehearn, Chris F.; Mighell, Alan J.

doi:10.1016/j.jaci.2015.08.051

Cited by 39 publications

(29 citation statements)

References 17 publications

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“…The most recent STIM1 mutation resulting in a dental defect was reported by Parry and colleagues in 2016 [50]. Two cousins were identified with a homozygous missense mutation (p.L74P) in the EF-hand domain of STIM1 .…”

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

confidence: 99%

“…This difference is less clear in patients with hypomineralized AI. Interestingly, although both cousins reported abnormal sweating suggesting anhydrosis, they both had normal hair and nails [50]. …”

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

confidence: 99%

“…Moreover, patients with mutations in STIM1 or ORAI1 do not always show signs of ED, as some patients showed obvious enamel defects but hairs or nails were normal (e.g. [50]). Thus, technically, STIM1 or ORAI1 mutations, as they are yet to be associated with ectoderm morphogenesis, given the similarity in phenotypic outcomes with ED, should be more appropriately described as ED-like for the time being to separate them from those whose etiologies are directly involved in ectoderm morphogenesis.…”

Section: Crac Channels and Ectodermal Dysplasiamentioning

confidence: 99%

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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%

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

confidence: 99%

Section: Crac Channels and Ectodermal Dysplasiamentioning

confidence: 99%

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CRAC channels in dental enamel cells

Eckstein

Lacruz

2018

Cell Calcium

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“…Ectodermal dysplasia in ORAI1 and STIM1-deficient patients is defined by defects in tooth development, specifically the calcification of dental enamel (amelogenesis imperfecta) and anhidrosis [24, 25, 53]. All patients with CRAC channelopathy reported to date uniformly have impaired sweat production when tested by pilocarpine iontophoresis [53, 82–85]. In many of these patients, anhidrosis or reduced sweat production (hypohidrosis) is apparent clinically and results in elevated body temperatures (hyperthermia), especially at high ambient temperature in hot summer months, and even in the absence of infections caused by the patients’ immunodeficiency.…”

Section: Effects Of Mutations In Human Genes That Impair Ca2+ Relementioning

confidence: 99%

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

Concepcion

Feske

2017

Cell Calcium

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Store-operated Ca2+ entry (SOCE) is a conserved mechanism of Ca2+ influx that regulates Ca2+ signaling in many cell types. SOCE is activated by depletion of endoplasmic reticulum (ER) Ca2+ stores in response to physiological agonist stimulation. After it was first postulated by J.W. Putney Jr. in 1986, SOCE has been described in a large number of non-excitable cell types including secretory cells of different exocrine glands. Here we discuss the mechanisms by which SOCE controls salt and fluid secretion in exocrine glands, with a special focus on eccrine sweat glands. In sweat glands, SOCE plays an important, non-redundant role in regulating the function of Ca2+-activated Cl− channels (CaCC), Cl− secretion and sweat production. In the absence of key regulators of SOCE such as the CRAC channel pore subunit ORAI1 and its activator STIM1, the Ca2+-activated chloride channel TMEM16A is inactive and fails to secrete Cl−, resulting in anhidrosis in mice and human patients.

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“…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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A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

Cited by 39 publications

References 17 publications

CRAC channels in dental enamel cells

CRAC channels in dental enamel cells

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

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

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A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency

Cited by 39 publications

References 17 publications

CRAC channels in dental enamel cells

CRAC channels in dental enamel cells

Regulation of epithelial ion transport in exocrine glands by store-operated Ca2+ entry

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

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