Alternative titles; symbols
HGNC Approved Gene Symbol: ORAI1
Cytogenetic location: 12q24.31 Genomic coordinates (GRCh38): 12:121,626,530-121,643,109 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.31 | Immunodeficiency 9 | 612782 | Autosomal recessive | 3 |
| Myopathy, tubular aggregate, 2 | 615883 | Autosomal dominant | 3 |
The ORAI1 (CRAMC1) gene encodes a plasma membrane protein essential for store-operated calcium entry (Vig et al., 2006).
Store-operated calcium (SOC) entry is mediated by calcium release-activated calcium (CRAC) channels following calcium ion release from intracellular stores. Feske et al. (2006) identified ORAI1, a protein crucial for store-operated calcium entry and CRAC channel function, using a combination of 2 unbiased genomewide approaches: a modified linkage analysis with SNP arrays, and a Drosophila RNAi screen designed to identify regulators of SOC entry and nuclear factor of activated T cells (NFAT; see 600489) nuclear import. The combination of these approaches identified ORAI1 as the single candidate gene for SCID with a primary defect in SOC entry and CRAC channel function in 2 patients. Feske et al. (2006) identified 3 human genes, designated ORAI1, ORAI2 (610929), and ORAI3 (610930), homologous to the Drosophila gene identified as a regulator of calcium entry in their study. In Greek mythology, the Orai are the keepers of the gates of heaven: Eunomia (Order or Harmony), Dike (Justice), and Eirene (Peace).
To identify genes encoding the CRAC channel or other proteins involved in its regulation, Vig et al. (2006) performed a genomewide RNA interference (RNAi) screen in Drosophila cells. They identified CRAC modulator-1 (Cracm1) as a novel gene essential for CRAC channel function. Vig et al. (2006) characterized the human ortholog of Cracm1, a 37.7-kD protein encoded by FLJ14466, which they called CRACM1. Immunofluorescence confocal analysis localized CRACM1 to the plasma membrane (PM), in keeping with the hydropathy profile of CRACM1, which predicted a topology of 4 transmembrane domains with both ends facing the cytosol.
McCarl et al. (2009) found expression of the ORAI1 gene in CD4+ and CD8+ T cells, CD19+ B cells, and in a subset of cells in the thymus, spleen, and tonsils. The ORAI1 gene was also expressed in sarcolemma of muscle fibers, eccrine sweat glands, and several other tissues, including skin, vascular endothelium, hepatocytes, lung, and kidney. It was not expressed in the brain.
Vig et al. (2006) showed that RNAi-mediated knockdown of human CRACM1 disrupted its activation. Overexpression of CRACM1 did not affect CRAC currents, suggesting that CRACM1, although necessary for CRAC activation, does not in and of itself generate significantly larger CRAC currents.
Yeromin et al. (2006) showed that interaction between wildtype STIM1 (605921) and ORAI, assessed by coimmunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce calcium ion store depletion. By site-directed mutagenesis, Yeromin et al. (2006) showed that a point mutation from glutamate to aspartate at position 180 in the conserved S1-S2 loop of ORAI transforms the ion selectivity properties of CRAC current from being Ca(2+)-selective with inward rectification to being selective for monovalent cations and outwardly rectifying. A charge-neutralizing mutation at the same position, glu to ala, acts as a dominant-negative nonconducting subunit. Yeromin et al. (2006) found that other charge-neutralizing mutants in the same loop express large inwardly rectifying CRAC current, and 2 of these exhibit reduced sensitivity to the channel blocker gadolinium (Gd). Yeromin et al. (2006) concluded that their results indicate that ORAI itself forms the calcium ion selectivity filter of the CRAC channel.
Independently, Prakriya et al. (2006) showed that ORAI1 is a PM protein, and that CRAC channel function is sensitive to mutation of 2 conserved acidic residues in the transmembrane segments. Glu106-to-asp (E106D) and glu190-to-gln (E190Q) substitutions in transmembrane helices 1 and 3, respectively, diminished calcium ion influx, increased current carried by monovalent cations, and rendered the channel permeable to cesium ion. Prakriya et al. (2006) concluded that these changes in ion selectivity provide strong evidence that ORAI1 is a pore subunit of the CRAC channel.
Soboloff et al. (2006) showed that coexpression of STIM1 and ORAI1 resulted in an enormous gain in function of SOC entry. Expression of ORAI1 alone inhibited SOC entry. Store-independent Ca(2+) entry was enhanced by coexpression of ORAI1 and STIM2 (610841), but not STIM1. Soboloff et al. (2006) concluded that ORAI1 is likely the channel entity mediating SOC function. They noted that the endoplasmic reticulum (ER) and PM localizations of STIM1 and ORAI1, respectively, are consistent with their roles as ER Ca(2+) sensor and PM Ca(2+) channel, respectively.
Independently, Mercer et al. (2006) showed that coexpression of STIM1 with ORAI1 resulted in enhanced SOC entry. Coexpression of STIM1 with ORAI2 augmented SOC entry to a lesser extent, while ORAI3 alone or with STIM1 had no effect on SOC entry, although it could rescue knockdown of ORAI1 function. Fluorescence and confocal microscopy demonstrated that STIM1 relocated from the ER to the vicinity of the PM following depletion of calcium stores, but it was not detected on the cell surface in the presence or absence of ORAI1. Mercer et al. (2006) proposed that STIM1 regulates or interacts with ORAI1 at sites of close apposition between the PM and an intracellular STIM1-containing organelle, such as the ER.
Luik et al. (2008) defined the relationships among ER calcium ion concentration, STIM1 redistribution, and CRAC channel activation and identified STIM1 oligomerization as a critical ER calcium ion concentration-dependent event that drives store-operated calcium ion entry. In human Jurkat leukemia T cells expressing an ER-targeted calcium indicator, CRAC channel activation and STIM1 redistribution followed the same function of ER calcium concentration, reaching half-maximum at about 200 micromolar with a Hill coefficient of approximately 4. Because STIM1 binds only a single calcium ion, the high apparent cooperativity suggested that STIM1 must first oligomerize to enable its accumulation at ER-plasma membrane (PM) junctions. To assess directly the causal role of STIM1 oligomerization in store-operated calcium ion entry, Luik et al. (2008) replaced the luminal calcium-sensing domain of STIM1 with the 12-kD FK506- and rapamycin-binding protein (FKBP12; 186945) or the FKBP-rapamycin binding domain of mTOR (601231). A rapamycin analog oligomerized the fusion proteins and caused them to accumulate at ER-PM junctions and activate CRAC channels without depleting calcium from the ER. Thus, Luik et al. (2008) concluded that STIM1 oligomerization is the critical transduction event through which calcium store depletion controls store-operated calcium entry, acting as a switch that triggers the self-organization and activation of STIM1-ORAI1 clusters at ER-PM junctions.
Using confocal microscopy, Lioudyno et al. (2008) demonstrated that both STIM1 and ORAI1 accumulated in the immunologic synapse of either activated or resting T cells in contact with antigen-pulsed dendritic cells. Ca(2+) concentrations were increased near the interface of the cells, and Ca(2+) signaling could be blocked by an ORAI1 dominant-negative mutant. Lioudyno et al. (2008) concluded that a positive feedback loop exists in which the initial T-cell receptor signal favors upregulation of STIM1 and ORAI1, which then augment Ca(2+) signaling during subsequent antigen encounter.
Using human constructs and cell lines, Muik et al. (2008) showed that STIM1 (605921) and ORAI1 interacted dynamically to activate PM Ca(2+) currents. ER store depletion caused STIM1-STIM1 multimerization at the ER, followed by STIM1-ORAI1 cluster formation at the ER-PM interface, and both interactions were reversed by store refilling. The C terminus of STIM1, when coexpressed with ORAI1, resulted in constitutive currents in the absence of STIM1-ORAI1 cluster formation and ER store depletion. Both N- and C-terminal deletion mutants of ORAI1 failed to generate Ca(2+) entry or currents upon ER store depletion; the C-terminal ORAI1 mutant failed to interact with STIM1, and the N-terminal ORAI1 mutant, which interacted with STIM1, exhibited a defect in channel gating.
By blocking SOC entry, but not receptor-operated calcium (ROC) entry mediated by TRPC channels (e.g., TRPC1; 602343), Liao et al. (2009) showed that ORAI1, when expressed at a level that enhanced SOC entry in HEK293 human embryonic kidney cells, led to the appearance of gadolinium-resistant ROC entry. ORAI1 with the immunodeficiency-associated arg91-to-trp (R91W; 610277.0001) mutation inhibited both ROC and SOC entry, as well as Ca(2+) entry elicited by TRPC3 (602345) activation, in HEK293 cells. Liao et al. (2009) proposed that SOC entry occurs through channels in lipid rafts, whereas ROC entry occurs outside of lipid rafts.
Yuan et al. (2009) reported the molecular basis for the gating of ORAI1 by STIM1. All ORAI channels were fully activated by a conserved STIM1 amino acid fragment (residues 344 to 442), which Yuan et al. (2009) termed STIM1 ORAI-activating region (SOAR). SOAR acted with STIM1 amino acids 450 to 485 to regulate the strength of the interaction with ORAI1. Activation of ORAI1 by SOAR recapitulated all the kinetic properties of activation with full-length STIM1. However, mutations within SOAR did not affect coclustering of STIM1 and ORAI1 in response to Ca(2+) store depletion, indicating that coclustering is not sufficient for ORAI1 activation. SOAR-mediated activation required an intact alpha-helical region at the C terminus of ORAI1. Deletion of N-terminal amino acids 1 to 73 of ORAI1 impaired activation by STIM1, but not by SOAR. In addition, inward rectification of ORAI1 was mediated by an interaction between the polybasic STIM1 residues 672 to 685 and a pro-rich region in the N terminus of ORAI1. Yuan et al. (2009) concluded that the essential properties of ORAI1 function can be understood by interactions with discrete regions of STIM1.
Wang et al. (2010) revealed a regulatory link between Orai channels and Ca(v)1.2 channels (see 114205) mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (Ca(v)1.2) channels while activating store-operated (Orai) channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with Ca(v)1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both Ca(v)1.2 and ORAI1 channels. Hence, STIM1 interacts with and reciprocally controls 2 major calcium channels hitherto thought to operate independently. Wang et al. (2010) concluded that such coordinated control of the widely expressed Ca(v)1.2 and Orai channels has major implications for calcium signal generation in excitable and nonexcitable cells.
Srikanth et al. (2010) found that CRACR2A (EFCAB4B; 614178) coimmunoprecipitated with ORAI1, ORAI2 (610929), ORAI3 (610930), and STIM1 (605921), suggesting that CRACR2A may have a role in store-operated calcium channels. Depletion of CRACR2A via small interfering RNA severely reduced stimulation-induced clustering between STIM1 and ORAI1. Depletion of CRACR2A in HEK293 cells or CRACR2B (EFCAB4A; 614177) in Jurkat human T cells also decreased store-operated calcium entry. Mutation analysis revealed that the EF hands of CRACR2A bound calcium and that calcium binding reduced the interaction of CRACR2A with ORAI1 and STIM1.
Feng et al. (2010) found that expression of the Ca(2+) transporting ATPase SPCA2 (ATP2C2; 613082) was upregulated in several human breast cancer cell lines and that upregulation was associated with elevated Ca(2+) signaling, cell proliferation, and tumorigenicity in nude mice. SPCA2 induced Ca(2+) influx was independent of both endoplasmic reticulum Ca(2+) stores and the ATPase activity of SPCA2. SPCA2 interacted with the store-operated Ca(2+) channel protein ORAI1. Knockdown of either SPCA2 or ORAI1 suppressed cell proliferation, colony formation, and tumorigenicity in MCF-7 breast cancer cells to a similar extent, and simultaneous knockdown did not confer additive effect. In cells overexpressing SPCA2, cell transformation and elevation of basal Ca(2+) levels were reversed by knockdown of ORAI1, consistent with a role for ORAI1 downstream of SPCA2. Coimmunoprecipitation and pull-down experiments with chimeric SPCA fragments revealed a 40-amino acid motif within the N terminus of SPCA2 that interacted with ORAI1, while the C terminus of SPCA induced cell transformation and constitutive Ca(2+) signaling. Feng et al. (2010) concluded that SPCA2 interacts with ORAI1 by its N terminus and activates ORAI1-dependent but store-independent Ca(2+) influx by its C terminus.
Using tandem affinity purification of Jurkat cells, followed by mass spectrometry, Krapivinsky et al. (2011) identified POST (SLC35G1; 617167) based on its copurification with ORAI1. Immunoprecipitation analysis confirmed that endogenous POST and ORAI1 interacted in Jurkat cells. Binding of POST to ORAI1 did not depend on ER Ca(2+) content. Confocal microscopy and coimmunoprecipitation analyses using transfected HEK293 cells and endogenous proteins in Jurkat cells showed that Ca(2+) depletion resulted in interaction of POST with STIM1 and translocation of POST-STIM1 to the cell periphery in juxtamembrane clusters. Knockdown or overexpression of POST had no effect on store-operated, STIM1-dependent ORAI1 activation. Store depletion promoted POST-dependent binding of STIM1 to SERCA2 (ATP2A2; 108740), PMCAs (e.g., ATP2B1; 108731), importin beta-1 (KPNB1; 602738), and exportin-1 (XPO1; 602559). Knockdown experiments showed that POST attenuated PMCA activity in store-depleted cells. Krapivinsky et al. (2011) concluded that, after Ca(2+) store depletion, high cytosolic Ca(2+) is sustained by ORAI1 activation and inhibition of PMCAs by the POST-STIM1 complex.
McNally et al. (2012) probed the central features of the STIM1 gating mechanism in the human CRAC channel protein, ORAI1, and identified the valine at residue 102 (V102), located in the extracellular region of the pore, as a candidate for the channel gate. Mutations in V102 produce constitutively active CRAC channels that are open even in the absence of STIM1. Unexpectedly, although STIM1-free V102 mutant channels are not Ca(2+)-selective, their Ca(2+) selectivity is dose-dependently boosted by interactions with STIM1. Similar enhancement of Ca(2+) selectivity is also seen in wildtype ORAI1 channels by increasing the number of STIM1 activation domains that are directly tethered to ORAI1 channels, or by increasing the relative expression of full-length STIM1. Thus, exquisite Ca(2+) selectivity is not an intrinsic property of CRAC channels but rather a tuneable feature that is bestowed on otherwise nonselective ORAI1 channels by STIM1. McNally et al. (2012) concluded that STIM1-mediated gating of CRAC channels occurs through an unusual mechanism in which permeation and gating are closely coupled.
Using a genomewide RNA interference screen in HeLa cells, Sharma et al. (2013) identified filamentous septin proteins, particularly SEPT4 (603696), as crucial regulators of store-operated Ca(2+) entry. Septin filaments and phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) rearrange locally at endoplasmic reticulum-plasma membrane junctions before and during formation of STIM1-ORAI1 clusters, facilitating STIM1 targeting to these junctions and promoting the stable recruitment of ORAI1. Septin rearrangement at junctions is required for PtdIns(4,5)P2 reorganization and efficient STIM1-ORAI1 communication. Septins demarcate specialized membrane regions such as dendritic spines, the yeast bud, and the primary cilium, and serve as membrane diffusion barriers and/or signaling hubs in cellular processes such as vesicle trafficking, cell polarity, and cytokinesis. Sharma et al. (2013) concluded that their data showed that septins also organize the highly localized plasma membrane domains that are important in STIM1-ORAI1 signaling, and indicated that septins may organize membrane microdomains relevant to other signaling processes.
Using linkage mapping by genomewide SNP array screen in 23 members of a family in which 2 sibs had immune dysfunction associated with impaired T-cell activation and CRAC channel dysfunction (612782), Feske et al. (2006) mapped the ORAI1 gene to chromosome 12q24.
Immunodeficiency 9
In 2 brothers with primary immunodeficiency-9 (IMD9; 612782) due to T-cell inactivation, previously reported by Feske et al. (1996), Feske et al. (2006) identified homozygosity for an R91W mutation in the ORAI1 gene (610277.0001). Expression of wildtype ORAI1 in SCID T cells restored store-operated calcium ion influx and the CRAC current (I-CRAC).
In the probands of the families with IMD9 reported by Partiseti et al. (1994) and Le Deist et al. (1995), McCarl et al. (2009) identified homozygous or compound heterozygous mutations in the ORAI1 gene (610277.0005-610277.0007). In vitro functional expression studies showed that the mutations resulted in a loss of function.
Tubular Aggregate Myopathy 2
In affected members of a family with autosomal dominant tubular aggregate myopathy-2 (TAM2; 615883), originally reported by Shahrizaila et al. (2004), Nesin et al. (2014) identified a heterozygous missense mutation in the ORAI1 gene (P245L; 610277.0002). The mutation was found by whole-exome sequencing. In vitro functional expression assays showed that the mutation suppressed slow calcium-dependent inactivation of ORAI1, consistent with a gain-of-function effect. The pathogenic mechanism was similar to that caused by STIM1 mutations in patients with TAM1 (160565).
In 6 patients from 3 unrelated Japanese families with TAM2, Endo et al. (2015) identified 2 different heterozygous missense mutations in the ORAI1 gene (G98S, 610277.0003 and L138F, 610277.0004). Patient-derived myotubes and HEK293 cells transfected with the mutations showed constitutive activation of store-operated CRAC channels independent of either calcium stores or STIM1 activation. The mutation in the first 2 families was found by whole-exome sequencing.
In a father and his 2 adult children, of Italian descent, with TAM2, Garibaldi et al. (2017) identified a heterozygous missense mutation in the ORAI1 gene (S97C; 610277.0008). In vitro functional expression studies in HEK293 cells showed that the variant resulted in increased rate of calcium entry, consistent with constitutive activation of the CRAC channel and a gain-of-function effect. Myotubes derived from 1 of the patients showed a similar increase in calcium entry and increased spontaneous oscillations compared to controls.
Bergmeier et al. (2009) generated transgenic mice expressing a blood cell-specific R93W mutation in the Orai1 gene, which is equivalent to the human R91W mutation. Mutant platelets showed defects in agonist-induced store-operated calcium entry and certain calcium-regulated platelet functions, such as integrin activation, granule release, and surface phosphatidylserine exposure. However, mutant platelets were able to aggregate and adhere to collagen under arterial flow conditions ex vivo, presumably because calcium release from intracellular stores was normal.
Henke et al. (2012) found that Stim1-knockout mouse embryonic fibroblasts (MEFs) and Orai1-knockdown MEFs were more susceptible than wildtype cells to oxidative stress, which could be rescued by Stim1 and Orai1 overexpression. Further studies with Stim1-knockout MEFs suggested that store-operated Ca(2+) entry and Stim1 are involved in regulation of mitochondrial shape and bioenergetics and that they play roles in oxidative stress.
In 2 sibs, born to consanguineous parents, with primary immunodeficiency-9 (IMD9; 612782) characterized by impaired T-cell activation (Feske et al., 1996), Feske et al. (2006) identified a 271C-T transition in the ORAI1 gene, leading to an arg91-to-trp (R91W) substitution at a conserved residue. Heterozygous carriers of the mutation showed reduced calcium influx.
Muik et al. (2008) showed that the R91W mutation impaired Ca(2+) current activation by ORAI1.
In affected members of a family with autosomal dominant tubular aggregate myopathy-2 (TAM2; 615883), originally reported by Shahrizaila et al. (2004), Nesin et al. (2014) identified a heterozygous c.734C-T transition in the ORAI1 gene, resulting in a pro245-to-leu (P245L) substitution at a highly conserved residue in the fourth transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. HEK293 cells transfected with the mutation showed induced CRAC current activation kinetics and peak size similar to wildtype, but the slow calcium-dependent current inactivation was reduced compared to wildtype; fast CDI was not affected. The findings were consistent with a gain-of-function effect.
In 5 patients from 2 unrelated Japanese families with tubular aggregate myopathy-2 (TAM2; 615883), Endo et al. (2015) identified a heterozygous c.292G-A transition (c.292G-A, NM_032790.3) in the ORAI1 gene, resulting in a gly98-to-ser (G98S) substitution at a highly conserved residue in the transmembrane 1 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Patient-derived myotubes and HEK293 cells transfected with the mutation showed constitutive activation of store-operated CRAC channels independent of either calcium stores or STIM1 (605921) activation; these findings were consistent with a gain of function.
In a Japanese man with tubular aggregate myopathy-2 (TAM2; 615883), Endo et al. (2015) identified a heterozygous c.412C-T transition (c.412C-T, NM_032790.3) in the ORAI1 gene, resulting in a leu138-to-phe (L138F) substitution at a highly conserved residue in the second transmembrane domain. The mutation was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases. HEK293 cells transfected with the mutation showed constitutive activation of store-operated CRAC channels independent of either calcium stores or STIM1 (605921) activation; these findings were consistent with a gain of function.
In a patient (P4), born of consanguineous French parents, with immunodeficiency-9 (IMD9; 612782), who was originally reported by Partiseti et al. (1994), McCarl et al. (2009) identified a homozygous 1-bp insertion (c.258_259insA, NM_032790) in exon 1 of the ORAI1 gene, resulting in a frameshift and premature termination (Ala88SerfsTer25) at the end of the first transmembrane domain. The mutation was not found in 2 healthy sibs or in 50 control individuals; DNA from the parents was unavailable. Northern blot analysis of patient cells showed undetectable mRNA, suggesting nonsense-mediated mRNA decay and a loss-of-function effect. Patient cells showed a defect in calcium influx that was rescued by transfection of wildtype ORAI1.
In a German boy (P6) with immunodeficiency-9 (IMD9; 612782), originally reported by Le Deist et al. (1995), McCarl et al. (2009) identified compound heterozygous mutations in exon 2 of the ORAI1 gene: a c.308C-A transversion (c.308C-A, NM_032790), resulting in an ala103-to-glu (A103E) substitution in the first transmembrane domain, and a c.581T-C transition, resulting in a leu194-to-pro (L194P; 610277.0007) substitution in the third transmembrane domain. The mutations, which segregated with the disorder in the family, were not found in 50 control individuals. Transfection of the mutations into HEK293 cells resulted in undetectable protein expression, suggesting a complete loss of function. Patient cells showed a defect in calcium influx that was rescued by transfection of wildtype ORAI1.
For discussion of the c.581T-C transition (c.581T-C, NM_032790) in the ORAI1 gene, resulting in a leu194-to-pro (L194P) substitution, that was found in compound heterozygous state in a patient with immunodeficiency-9 (IMD9; 612782) by McCarl et al. (2009), see 610277.0006.
In a father and his 2 adult children, of Italian descent, with autosomal dominant tubular aggregate myopathy-2 (TAM2; 615883), Garibaldi et al. (2017) identified a heterozygous c.290C-G transversion (c.290C-G, NM_032790.3) in the ORAI1 gene, resulting in a ser97-to-cys (S97C) substitution at a highly conserved residue in the M1 domain. The mutation was not found in the ExAC or Exome Variant Server database. In vitro functional expression studies in HEK293 cells showed that the variant resulted in increased rate of calcium entry, consistent with constitutive activation of the CRAC channel and a gain-of-function effect. Myotubes derived from 1 of the patients showed a similar increase in calcium entry and increased spontaneous oscillations compared to controls.
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