A novel hypomorphic mutation in STIM1 results in a late-onset immunodeficiency

Schaballie, Heidi; Rodriguez, Rémy; Martin, Emmanuel; Moens, Leen; Frans, Glynis; Lenoir, Christelle; Dutré, Joris; Canioni, Danielle; Bossuyt, Xavier; Fischer, Alain; Latour, Sylvain; Meyts, Isabelle; Pïcard, Capucine

doi:10.1016/j.jaci.2015.03.009

Cited by 49 publications

(57 citation statements)

References 8 publications

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“…T cells of patients with null muations in ORAI1 or STIM1 lack SOCE and IL-2 production upon TCR stimulation. However, addition of exogenous IL-2 has had variable effects on their ability to proliferate in vitro (Feske et al, 1996; Fuchs et al, 2012; Picard et al, 2009; Schaballie et al, 2015). Similarly, the proliferation of murine T cells lacking STIM1 and STIM2 could not be restored by exogenous IL-2 in vitro and they failed to proliferate in response to LCMV infection in vivo even when transferred to immunocompetent (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the proposed mechanisms involve regulation of the ‘growth factor’ interleukin-2 (IL-2) and cyclins or cyclin-dependent kinases, which in some cell types depend on calcineurin and NFAT signaling (Mognol et al, 2016). Although IL-2 promotes T cell proliferation in vitro in an auto- or paracrine fashion, addition of exogenous IL-2 to T cells from patients with null mutations in ORAI1 or STIM1 or T cells from Orai1 fl/fl Cd4Cre Orai2 −/− mice only weakly rescues TCR-induced proliferation in vitro (Feske et al, 1996; Fuchs et al, 2012; Le Deist et al, 1995; Picard et al, 2009; Schaballie et al, 2015; Vaeth et al, 2017). Another possible mechanism by which SOCE may control T cell proliferation is through the regulation of metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

et al. 2017

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SUMMARY Store-operated Ca2+ entry (SOCE) is the main Ca2+ influx pathway in lymphocytes and essential for T cell function and adaptive immunity. SOCE is mediated by Ca2+ release-activated Ca2+ (CRAC) channels that are activated by stromal interaction molecules (STIM) 1 and STIM2. SOCE regulates many Ca2+-dependent signaling molecules including calcineurin and inhibition of SOCE or calcineurin impairs antigen-dependent T cell proliferation. We here report that SOCE and calcineurin regulated cell cycle entry of quiescent T cells by controlling glycolysis and oxidative phosphorylation. SOCE directed the metabolic reprogramming of naive T cells by regulating the expression of glucose transporters, glycolytic enzymes and metabolic regulators through the activation of nuclear factor of activated T cells (NFAT) and the PI3K-AKT kinase-mTOR nutrient sensing pathway. We propose that SOCE controls a critical ‘metabolic checkpoint’ at which T cells assess adequate nutrient supply to support clonal expansion and adaptive immune responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

et al. 2017

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“…Upon Ca 2+ depletion in the SR, the SOCE pathway is activated to replenish the cytosolic Ca 2+ stores, which is important during prolonged tetanic stimulation and fatigue [43,52,53,54,55,56,57]. The luminal cEFh domain of STIM1 loses the Ca 2+ binding and undergoes conformational changes to the unfolded form, exposing hydrophobic residues [58,59].…”

Section: Store-operated Calcium Entrymentioning

confidence: 99%

“…Affected individuals with loss-of-function mutations in these genes are known to have severe combined immunodeficiency (SCID), characterized by a defect in T-cell activation, recurrent infections [43,45,46], ectodermal dysplasia [47,48], abnormal enamel [43,45,47,52], and muscle hypotonia [43,52,54,56,57]. Transgenic mice with muscle-specific expression of dominant negative ORAI1 have been reported to exhibit reduced body weight, muscle mass, and fiber cross-sectional area [58].…”

Section: Store-operated Calcium Entrymentioning

confidence: 99%

Calcium Dyshomeostasis in Tubular Aggregate Myopathy

Lee

Noguchi

2016

IJMS

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Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca2+ in myofibers. Upon excitation, it releases Ca2+ into the cytosol, inducing contraction of myofibrils. During relaxation, it takes up cytosolic Ca2+ to terminate the contraction. During exercise, Ca2+ is cycled between the cytosol and the SR through a system by which the Ca2+ pool in the SR is restored by uptake of extracellular Ca2+ via a specific channel on the plasma membrane. This channel is called the store-operated Ca2+ channel or the Ca2+ release-activated Ca2+ channel. It is activated by depletion of the Ca2+ store in the SR by coordination of two main molecules: stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (ORAI1). Recently, myopathies with a dominant mutation in these genes have been reported and the pathogenic mechanism of such diseases have been proposed. This review overviews the calcium signaling in skeletal muscles and role of store-operated Ca2+ entry in calcium homeostasis. Finally, we discuss the phenotypes and the pathomechanism of myopathies caused by mutations in the STIM1 and ORAI1 genes.

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“…Chou and coauthors 41 presented a patient with refractory cytomegalovirus infection and hypotonia, with normal T cell number and mitogen-stimulated proliferation, in whom a frameshift mutation in calcium release-activated calcium modulator 1 (ORAI) was found. Schaballie et al 42 reported two siblings with recurrent infections, refractory inflammatory colitis, psoriasis and myopathy. They identified a homozygous missense mutations in stromal interaction molecule 1 (STIM1) resulting in residual expression and function.…”

Section: Clinical Immunological Phenotypes Associated With Gene Mutatmentioning

confidence: 99%

Advances in clinical immunology in 2015

Chinen

Notarangelo

Shearer

2016

Journal of Allergy and Clinical Immunology

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Advances in clinical immunology in the past year included the report of practice parameters for the diagnosis and management of primary immune deficiencies (PIDs) to guide the clinician in the approach to these relatively uncommon disorders. We have learned of new gene defects causing immunodeficiency and of new phenotypes expanding the spectrum of conditions caused by mutations found in one gene, such as a specific RTEL1 mutation causing isolated NK cell deficiency, and mutations in RAB27 resulting in immunodeficiency without albinism. Advances in diagnosis included the increasing use of whole exome sequencing to identify gene defects, and the measurement of serum free light chains to identify secondary hypogammaglobulinemias. For several PIDs, improved outcomes have been reported after definitive therapy with hematopoietic stem cell transplantation and gene therapy.

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A novel hypomorphic mutation in STIM1 results in a late-onset immunodeficiency

Cited by 49 publications

References 8 publications

Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

Store-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming

Calcium Dyshomeostasis in Tubular Aggregate Myopathy

Advances in clinical immunology in 2015

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