The Ca2+ Sensor STIM in Human Diseases: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Juan Antonio Rosado.

The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca2+ entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca2+ sensors in the endoplasmic reticulum (ER) and, upon Ca2+ store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca2+ signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. 

  • STIM1
  • STIM2
  • store-operated Ca2+ entry
  • Orai

1. Disorders Associated with Gain-of-Function STIM1 Mutations

As mentioned above, STIM1 is involved in a plethora of cellular functions and a number of disorders have been associated with STIM1 mutations that lead to either gain- or loss-of-function resulting in constitutive activation of CRACs or deficient Ca2+ influx upon depletion of the intracellular Ca2+ stores. Among the most relevant disorders associated with gain-of-function mutations of STIM1 are Stormorken syndrome, York platelet syndrome (YPS), and tubular aggregate myopathy (TAM).

1.1. Stormorken Syndrome and Tubular Aggregate Myopathy (TAM)

The Stormorken syndrome is a rare autosomal-dominant genetic condition identified by Helge Stormorken in 1984 in a patient suffering from long-lasting bleeding after a minor accident [46][1]. This syndrome is characterized by bleeding diathesis, thrombocytopenia, congenital miosis, mild anemia, asplenia, headache, ichthyosis, and proximal muscle weakness. One of the most relevant features of this syndrome is the platelet phenotype. While platelets from normal subjects exhibit a very low resting cytosolic free Ca2+ concentration, which is significantly elevated upon stimulation with physiological agonists, leading to exposure of phosphatidylserine at the plasma membrane [47,48][2][3], Stormorken platelets show significantly elevated resting cytosolic Ca2+ concentration and reduced or absent SOCE upon Ca2+ store depletion, which has been attributed to near-maximal Orai1 activation at resting conditions [41][4]. Therefore, platelets from Stormorken patients are in a pre-activated or procoagulant state, leading to prothrombotic predisposition and thrombocytopenia. Consistent with this, non-stimulated platelets from Stormorken patients exhibit increased levels of CD63 and p-selectin at the plasma membrane, as well as alpha granule secretion, which are well-known markers of activation [49][5]. Paradoxically, it could be expected that constitutive SOCE and procoagulant platelet activity in Stormorken patients might result in an enhanced incidence of thromboembolisms; however, this functional disorder leads to patients with mild bleeding resulting from a reduced platelet cohesion as determined under shear stress conditions both in vivo and ex vivo [41,50][4][6]. This phenotype is similar to that exhibited by mice bearing the activating STIM1 EF-hand mutation D84G [51][7].
Almost three decades after the identification of this condition, the molecular basis of the syndrome was identified as a gain-of-function mutation located in the α2 segment of the STIM1 coiled-coil region 1 (CC1), the STIM1-R304W [41,49,52][4][5][8]. The missense mutation occurs in exon 7 of STIM1 (c.910C>T). Expression of the STIM1-R304W mutant in zebrafish resulted in thrombocytopenia, bleeding, and hypoplastic caudal vein, a phenotype that is reminiscent of the Stormorken syndrome in humans [52][8]. As mentioned above, one of the functions of the STIM1 CC1 domain is to keep STIM1 in a tight and compact state at high ER Ca2+ concentrations. This mechanism depends on the formation of a coiled-coil clamp involving the CC1 and CC3 domains [32,53][9][10]. Although the precise mechanism has not been fully elucidated, it has been reported that STIM1 carrying the R304W mutation at the end of the CC1α2 segment exhibits CC1 homomerization and elongation of CC1, thus preventing CC1−CC3 clamp formation and maintaining STIM1 in a constitutively active state in the absence of Ca2+ store depletion [36][11]. Consistent with this, NIH3T3 murine fibroblasts transfected with mouse STIM1-R304W fused with yellow fluorescent protein (YFP) showed increased clustering of YFP signal at resting conditions than STIM1-WT, which was evenly distributed in the ER, thus indicating constitutive STIM1 aggregation and subsequent activation [54][12]. In addition to the STIM1-R304W mutation, the R304Q has also been reported in a smaller number of patients. This mutation causes a milder clinical form of Stormorken syndrome as compared to patients bearing the R304W mutation [55][13].
In 2021, the genetic analysis of a 12-year-old Chinese female with Stormorken-like symptoms identified a novel heterozygous missense mutation (c.1095G>C transition) leading to a STIM1 K365N amino acid substitution [55][13]. This mutation is located in the CC2 domain and affects directly the SOAR/CAD region involved in the activation of Orai1. This new STIM1 mutation widens the spectrum of STIM1 variants causing Stormorken syndrome.
The Stormorken syndrome clinically overlaps with TAM, a progressive muscle disorder associated with weakness, cramps, myalgia, increased creatine kinase levels, and accumulation of packed membrane tubules containing sarcoplasmic reticulum proteins. These tubules are observed by electron microscopy as straight, single- or double-walled tubules that are highly ordered and aligned in parallel in a longitudinal muscle section [56,57][14][15]. Furthermore, TAM is characterized by large variations in fiber size, increased number of fibers with internalized nuclei, as well as type 1 fiber predominance [58][16]. Most patients with Stormorken syndrome exhibit TAM. Furthermore, TAM is present in a non-syndromic form of TAM as well as in the Stormorken-like syndrome, which lacks miosis and hematological disorders [59][17]. The most typical clinical manifestation is proximal muscle weakness in lower limbs followed by extraocular muscle weakness [60][18].
TAM is mediated by several autosomal dominant mutations in the EF-hand domain of STIM1, which result in constitutive CRAC activation. Initially, four activating STIM1 mutations were identified through Sanger sequencing of the STIM1 coding exons and exon–intron boundaries in families of patients with common histological features or by exome sequencing of TAM patients: H72Q, D84G, H109N, and H109R. Expression of all the STIM1 mutants in C2C12 myoblasts resulted in constitutive STIM1 oligomerization and clustering, thus demonstrating constitutive activation of STIM1 [60][18]. Further studies from the same group identified four novel STIM1 EF-hand mutations in six new TAM families: N80T, L96V, F108I, and F108L. As for the above-mentioned STIM1 EF-hand mutations, the additional mutations were shown to induce STIM1 clustering in C2C12 myoblasts independently of changes in the ER Ca2+ concentration [61][19]. Two more STIM1-activating mutations were identified in TAM patients, the STIM1-I115F [62][20] and STIM1-G81D [63][21]. In contrast to the other TAM STIM1 mutations, myoblasts from patients bearing the G81D mutation did not show an abnormally increased basal cytosolic Ca2+ concentration but the amplitude of SOCE was significantly higher in TAM vs. control myoblasts [63][21].
TAM might also be caused by mutations in other proteins, including Orai1 and the reticular Ca2+-handling protein calsequestrin-1. Three missense mutations in the calsequestrin-1 gene have been identified in patients with a mild phenotype associated with tubular aggregate myopathy, including D44N, G103D, and I385T [64][22]. Furthermore, the Orai1 mutation P245L located in the fourth transmembrane domain has been associated with a Stormorken-like syndrome showing congenital miosis and TAM but lacking hematological abnormalities [52][8].

1.2. York Platelet Syndrome (YPS)

The York platelet syndrome was first reported in a series of articles published in 2003 describing ultrastructural abnormalities found in platelets from a woman and her male child who manifested life-long thrombocytopenia although functionally normal in aggregation [65,66,67,68][23][24][25][26]. The patients exhibit slightly enlarged platelets with the presence of two giant organelles that originate in megakaryocytes and fully develop in circulating platelets, the opaque organelles, large electron opaque bodies, and the target organelles made up of multiple layers resembling a target [69][27]. Analytical electron microscopy revealed that these aberrant organelles contain large amounts of Ca2+ and phosphorous, in a ratio that resembles that observed in normal platelet dense bodies, as well as peroxidase and acid phosphatase activity, like primary lysosomes. As the number of lysosomes was reduced in YPS platelets, it has been reported that both opaque and target organelles are either abnormal lysosomes or fused with lysosomes during their development [67][25]. Some platelets contain a normal number of alpha granules, while others present a fewer number or lack this organelle [69][27]. In addition to the mentioned platelet features, the YPS patients exhibit myopathy characterized by the presence of degenerating and regenerating fibers and an increased number of myofibers with internalized nuclei [69,70][27][28].
Whole exome sequencing from YPS patients revealed two STIM1 variants, c.343A>T and c.910C>T, encoding for the STIM1 mutations I115F and R304W, respectively [69,70][27][28]. These two mutations have also been recognized as activating STIM1 mutations in TAM and Stormorken syndrome, respectively (see above). In fact, YPS patients have been reported to present tubular aggregates, which is not surprising given the genotypic overlap with TAM and Stormorken syndrome [71][29].
A recent study [72][30] has reported five novel STIM1 mutations not related to TAM, Stormorken syndrome, or YPS but leading to muscle phenotype in individuals between 26 and 57 years old. The reported STIM1 variants c.312A>T, c.412G>A, c.1889C>T, c.2246G>A, and c.1894_1897del encode for the STIM1 mutations K104N, located in the non-canonical EF-hand region, V138I, located in the SAM domain, S630F (in the longer STIM1 isoform (STIM1L) sequence [73][31]) and R749H (STIM1L), located in C-terminal regions not associated with functional domains, as well as a single frameshift variant, H632fs (STIM1L), lacking the cytosolic proline/serine-rich domain and the polybasic C-terminal region, respectively. Patients bearing these mutations manifested muscle disorders. The patient with K104N showed tubular aggregates, the V138I was associated with congenial fiber type size disproportion, S630F and R749H were associated with type I fiber atrophy and severe muscle dystrophy with inflammatory infiltrates, respectively, and the H632fs mutation was associated with mild variation in fiber size [72][30]. Functional analysis of SOCE in HEK293 cells expressing STIM1 WT or the STIM1 mutants K104N, V138I, S630F, and R749H has revealed that all the mutations enhance SOCE, especially the V138I and S630F mutations [72][30]. Furthermore, all these mutations have been reported to enhance significantly the resting cytosolic Ca2+ concentration when expressed in HEK293 cells [74][32], thus suggesting that these novel STIM1 mutants are gain-of-function variants. There is no further functional analysis of the STIM1-H632fs mutant.
The aberrant SOCE mediated by the aforementioned gain-of-function STIM1 mutations, as well as some gain-of-function Orai1 variants, with the exception of the R304Q, has been recently reported to be sensitive to two structurally unrelated SOCE modulators, CIC-37, a compound developed from a class of pyrazole-bearing molecule, and CIC-39, a biphenyl-triazole developed from Synta66 [74][32]. If these compounds prove to be tolerable in clinical trials, like other SOCE modulators [75[33][34],76], their applicability in the treatment of Stormorken syndrome, TAM, and YPS will be of great relevance.

2. Disorders Associated with Loss-of-Function STIM1 Mutations

CRACs are formed by the heterogeneous association of Orai and STIM family members. Twenty years ago, the study of STIM1 and Orai1 loss-of-function mutations allowed the identification of the molecular mediator of SOCE [15][35]. Indeed, due to their highly similar phenotypic traits, the syndromes arising from STIM1 and Orai1 loss-of-function mutations are grouped under the name of CRAC channelopathy [77][36]. Although SOCE is a ubiquitous mechanism in human physiology, patients suffering from CRAC channelopathy present a limited spectrum of symptoms that include severe combined immunodeficiency-like disease with chronic infections and autoimmunity, ectodermal dysplasia, abnormal enamel, anhidrosis, mydriasis, and muscular hypotonia [3,59][17][37]. This discrepancy reflects the inability of some cells to compensate for the loss of Orai1 or STIM1 function, an issue that undisturbed tissues might solve by using other family members or by adapting an alternative signaling mechanism.
Up to date, six autosomal recessive STIM1 loss-of-function mutations have been described. STIM1 E128R (E128fs*9) mutation results from an adenine insertion after position 380 in the STIM1 gene. Due to the appearance of a premature termination codon, this frameshift produces a truncated STIM1 mutant that ends at the beginning of the SAM domain. The STIM1 E128fs*9 patients’ derived fibroblasts showed markedly reduced STIM1 mRNA levels and an undetectable STIM1 protein expression, making these cells unable to mediate SOCE [78][38]. Patients suffering from this mutation present a similar phenotype to those with Orai1 deficiency, which is characterized by autoimmune hemolytic anemia and immune thrombocytopenia, hepatosplenomegaly, lymphadenopathy, hypoglycemia, and nonprogressive muscular hypotonia. Byun et al. described another STIM1 null mutation originated by guanine to alanine substitution at the −1 position of STIM1 exon 8 (1538-1G>A) [79][39]. This mutation was found in a child who died from Kaposi sarcoma at two years of age, a neoplasm caused by human herpesvirus (HHV)-8 infection [80][40]. In patient-derived EBV-transformed B cells, the STIM1 1538-1G>A substitution induces the formation of abnormally spliced STIM1 mRNA variants and the inability to synthesize functional STIM1 proteins, a condition that abrogates SOCE in these cells [79][39]. Based on this information, authors claimed that the STIM1 1538-1G>A null mutation may have induced T-cell deficiency in this patient, a condition that favored the opportunistic HHV8 infection and the rapid progression of Kaposi sarcoma.
CRAC channelopathy derived from STIM1 P165Q mutation shows a unique phenotypic trait. This mutation reduced STIM1 expression and function but might still allow for residual SOCE [81][41]. Although the functional consequences of P165Q mutation are unknown, it has been proposed that this modification impairs STIM1 function by impeding SAM domain homomerization, a key step in the activation mechanism of this protein [30][42]. Interestingly, the residual Ca2+ entry observed in T cells derived from STIM1 P165Q patients might support immune responses, increasing their lifespan compared to other CRAC channelopathy patients. Furthermore, this hypomorphic mutation has been associated with additional inflammatory disorders, such as psoriasis and colitis, that were not previously associated with other STIM1 mutations.
Two loss-of-function mutations have been described within the SOAR/CAD domain of STIM1. As described above, this sequence plays a crucial role in the oligomerization of STIM molecule and the activation of store-operated Ca2+ channels. STIM1 R429C mutation was found in two siblings born to consanguineous parents. A younger sister died from sepsis at the age of 21 months, while the older presented dental enamel defect, anhidrosis, generalized eczema, mild muscular hypotonia, light-insensitive pupils, primary enuresis, and combined immunodeficiency. Interestingly, STIM1 R429C mutation did not alter protein expression but impaired SOCE in regulatory and CD3+ T cells [82][43]. A study on the structural consequences of the STIM1 R429C mutation revealed that this modification destabilizes the CC3 domain, thus inducing the extension of the C-terminal region of the protein and the release of the STIM1 polybasic domain. These alterations promote the constitutive translocation of STIM1 to ER-PM junctions, impair STIM1 oligomerization, and abrogate its ability to activate the Orai1 channel [83][44]. Wang et al. described a case where the STIM loss-of-function mutation R426C leads to a mild clinical phenotype characterized by enamel defects with rapid dental attrition, nail dysplasia, and frequent throat infections [84][45]. Like STIM1 R429, R426 is involved in the regulation of STIM1 C-terminus conformational state, a role that assures the stability of this region at resting and following the depletion of reticular Ca2+ stores [53][10]. The STIM1 R426C mutation has been reported to destabilize the CC1-SOAR clamp but also to attenuate moderately the interaction of STIM1 with Orai1, thus reducing the Orai1 currents [85][46]. The latter provides an explanation for the phenotype reported by Wang et al. [84][45].
A novel STIM1 loss-of-function mutation was identified in two patients affected with muscle weakness, dysmorphic facies, hypoplastic patellae, dental abnormalities, and hyperelasticity. This phenotype, which only presents mild immune deficiencies, was caused by a guanine insertion after position 685 in the coding sequence of STIM1, a frameshift that changes phenylalanine 229 to leucine and induces a premature termination codon. As observed in other STIM1 null mutations, cells derived from patients carrying STIM1 F229L mutation show reduced STIM1 mRNA levels and an indetectable protein expression [86][47]. However, the authors did not assay SOCE in patient-derived immune cells, information that might help to clarify the wide phenotypic spectrum evoked by STIM1 loss-of-function mutations.

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