STIM1 Deficiency

Mendelian MONDO:0013008 Pathograph 38 Show in embeddings browser Primary Immunodeficiency Combined Immunodeficiency Channelopathy

STIM1 deficiency is an autosomal recessive CRAC (calcium release-activated calcium) channelopathy. STIM1 is the endoplasmic reticulum calcium sensor that detects store depletion and gates ORAI1, the pore-forming subunit of the plasma membrane CRAC channel. Biallelic loss-of-function STIM1 variants abolish store-operated calcium entry (SOCE), so calcineurin is not activated and the NFAT-dependent transcriptional programme is not induced. Lymphocyte numbers and development are essentially normal; what fails is lymphocyte function, which is why the disease is a combined immunodeficiency rather than a classical T-negative severe combined immunodeficiency. The clinical syndrome combines life-threatening infection in the first years of life, including chronic herpesvirus infection and herpesvirus-driven malignancy, with congenital non-progressive muscular hypotonia, ectodermal dysplasia with defective dental enamel and hypohidrosis, and partial iris hypoplasia or mydriasis. Two features distinguish it from its sibling disease ORAI1 deficiency: lymphoproliferation with hepatosplenomegaly and lymphadenopathy is common, and autoimmune cytopenias, usually Coombs-positive haemolytic anaemia and thrombocytopenia in the first year of life, are usual rather than exceptional. Both track with reduced numbers of FOXP3-positive regulatory T cells and invariant natural killer T cells, which are the only lymphocyte populations consistently reduced. Allogeneic haematopoietic stem cell transplantation addresses the immunological arm and is what the severe cases require; the myopathic, ectodermal and ocular arms are cell-intrinsic to non-haematopoietic tissue and persist after transplantation. The disease is ultra-rare, and the published phenotype is wide at the mild end: two cousins homozygous for a missense EF-hand allele had grossly abnormal lymphocyte calcium entry without overt clinical immunodeficiency, and two siblings with a frameshift allele abolishing STIM1 protein presented with a connective-tissue and skeletal picture rather than with severe immune disease.

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Classifications

IUIS Category

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Inheritance

Autosomal recessive HP:0000007

Reported patients are homozygous for loss-of-function STIM1 alleles, in several instances from consanguineous kindreds. Heterozygous parents and siblings are clinically unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx."

Establishes homozygosity for a single STIM1 nonsense allele in the founding kindred, that is, autosomal recessive inheritance.

Discussions and Knowledge Gaps

Why does complete loss of STIM1 protein not predict the severity of the immunodeficiency?

KNOWLEDGE GAP stim1_protein_loss_does_not_predict_severity

Attached to

pathophysiology#Biallelic Loss-of-Function STIM1 Variants

Two siblings homozygous for a frameshift allele that abolishes STIM1 protein presented with a connective-tissue and skeletal picture rather than with severe immune disease, while missense alleles that leave protein expressed have produced fatal infection in infancy. So neither the allele class nor the presence of protein orders the clinical severity. The obvious candidate is the paralog STIM2, which has a lower activation threshold and is intact in these patients, but no study has tested whether STIM2 levels track the clinical severity in human patients.

Is autoimmunity genuinely commoner in STIM1 deficiency than in ORAI1 deficiency, or is the difference an artefact of cohort size and early death?

KNOWLEDGE GAP stim1_vs_orai1_autoimmunity_difference

Attached to

pathophysiology#Loss of Peripheral Immune Tolerance

The two diseases are otherwise near-identical, and lymphoproliferation and autoimmune cytopenias are the one axis on which they are reported to differ. The review that reports the difference also says it cannot be settled, because the ORAI1 patients are few and several died before the age at which STIM1-deficient patients develop cytopenias. Settling it needs either more ORAI1 patients or longer follow-up of transplanted ones, not a new experiment.

Does impaired activation-induced T cell death actually drive the lymphoproliferation?

KNOWLEDGE GAP aicd_impairment_and_lymphoproliferation

Attached to

pathophysiology#Impaired Activation-Induced T Cell Death

This is the standard explanation for the paradox that a disease of failed T cell activation produces T cell accumulation, and the patient data are mixed: apoptosis after CD3 stimulation was impaired in one STIM1-deficient patient and normal in two others. The review itself puts it no higher than "likely contributes". Until it is measured in more patients, the edge from this node to the lymphoproliferation stays typed as having unidentified intermediates.

Why does the STIM1-null mouse die perinatally of skeletal myopathy when protein-null human patients survive with a non-progressive hypotonia?

HUMAN MODEL MISMATCH stim1_null_mouse_muscle_severity_mismatch

Attached to

animal_models#Mouse pathophysiology#Impaired Skeletal Muscle Calcium Handling

The direction of the mismatch is what makes it interesting: the model is more severe than the disease, not less. Mice lacking functional STIM1 die perinatally of a skeletal myopathy, while patients with frameshift alleles that abolish STIM1 protein reach adulthood with a static hypotonia and no structural abnormality on biopsy. Something compensates in human muscle and not in mouse muscle, and until that is identified the mouse cannot be used to predict how far the human muscle phenotype could be corrected.

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Pathophysiology

Biallelic Loss-of-Function STIM1 Variants

Homozygous STIM1 variants. Reported alleles include a nonsense change in exon 3, a splice-site change, the frameshift c.685delT, and the missense alleles p.L74P (EF-hand), p.L195P and p.R429C (coiled-coil domain 3). Nonsense, splice and frameshift alleles abolish STIM1 protein outright; the missense alleles leave protein expressed but unable to sense store depletion or to gate ORAI1, so null and functionally-null genotypes converge on the same cellular lesion.

STIM1 hgnc:11386 ⇓ LOSS OF FUNCTION

Genetic context variant_origin: GERMLINE allelic_event: NONSENSE_VARIANT allelic_event: MISSENSE_VARIANT allelic_event: FRAMESHIFT_VARIANT allelic_event: SPLICE_SITE_VARIANT zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Germline biallelic STIM1 alleles. Both protein-abolishing (nonsense, splice-site, frameshift) and expression-preserving but function-abolishing (missense) mechanisms are represented.

calcium channel regulator activity GO:0005246 ⇓ LOSS OF FUNCTION

Downstream

Loss of ER Calcium Store Sensing and CRAC Channel Gating Absent or non-functional STIM1 cannot detect endoplasmic reticulum calcium depletion or gate ORAI1.

Show evidence (4 references)

PMID:19420366 SUPPORT Human Clinical

"Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx."

The founding allele, and the statement that it removes both STIM1 protein and calcium influx, which is what makes loss of function the disease mechanism.

PMID:22190180 SUPPORT Human Clinical

"We report two patients with a homozygous R429C point mutation in STIM1 completely abolishing store-operated calcium entry in T cells."

Extends the allelic spectrum to a missense allele that abolishes SOCE, establishing that an expressed but non-functional protein produces the same cellular lesion.

PMID:33733462 SUPPORT Human Clinical

"Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1"

A frameshift allele, c.685delT, abolishing STIM1 protein, which is the second protein-null mechanism in the allelic spectrum. The quote stops before the variant nomenclature because the reference validator strips bracketed spans before matching, so the protein-level description in square brackets cannot be quoted without a `literal_bracket_patterns` entry in `conf/reference_validator_config.yaml`. The item below carries the complete-loss claim from the same abstract.

+ 1 more reference

Loss of ER Calcium Store Sensing and CRAC Channel Gating

STIM1 is the endoplasmic reticulum calcium sensor of the CRAC channel complex. Its luminal EF-hand binds ER calcium; on store depletion STIM1 oligomerizes, translocates to ER-plasma membrane junctions and gates ORAI1 through its cytoplasmic coiled-coil domains. Without functional STIM1 there is no signal from the depleted store to the pore, so the CRAC channel is never opened even though ORAI1 itself is intact. That the lesion is STIM1 and not a correlated defect is established by rescue: expressing wild-type STIM1 in patient cells restores calcium influx.

calcium channel regulator activity GO:0005246 ⇓ LOSS OF FUNCTION

Downstream

Abolished Store-Operated Calcium Entry With no gating signal reaching ORAI1, store depletion no longer produces sustained calcium influx.

Show evidence (1 reference)

PMID:20876309 SUPPORT In Vitro

"STIM1 mRNA splicing, protein production, and Ca(2+) influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1."

The rescue result establishes that loss of STIM1 is what removes calcium influx in patient cells, rather than a correlated abnormality.

Abolished Store-Operated Calcium Entry

Store-operated calcium entry is the dominant sustained calcium influx pathway in lymphocytes, and it is also required in skeletal muscle, ameloblasts and eccrine sweat gland cells. Its loss is demonstrable in patient T cells, NK cells, B cell lines and fibroblasts, and is the single cellular lesion from which every arm of the disease follows. STIM1 is near-ubiquitously expressed, so the lesion is present in far more tissues than are clinically affected: the restriction of the phenotype reflects where SOCE is non-redundant, not where STIM1 is expressed.

T cell CL:0000084 natural killer cell CL:0000623 fibroblast CL:0000057

store-operated calcium entry GO:0002115 ↓ DECREASED

Downstream

Failure of Calcineurin-NFAT Dependent Transcription Sustained cytosolic calcium is required to activate calcineurin; without it NFAT remains phosphorylated and cytoplasmic.

Impaired NK Cell Cytotoxic Function NK cell granule exocytosis and interferon-gamma production are calcium-dependent and fail in patient cells.

Impaired Skeletal Muscle Calcium Handling Loss of SOCE in skeletal muscle fibres, where it refills sarcoplasmic reticulum calcium stores during sustained activity.

Defective Enamel Mineralization Ameloblasts depend on store-operated calcium influx for the calcium handling and secretory function that mineralize enamel.

Sweat Gland Secretory Failure Eccrine sweat gland secretion requires SOCE to activate the calcium-activated chloride channel that drives fluid secretion.

Mydriasis Mydriasis is reported alongside the iris hypoplasia, by the same route and with the same uncertainty about the intermediate.

Hypoplasia of the iris Partial iris hypoplasia and mydriasis are reported in several patients. The route is left unspecified: the 2015 review reads them as a further sign of the muscular hypotonia, which would place them downstream of smooth rather than skeletal muscle calcium handling, and no study has identified the intermediate.

Show evidence (2 references)

PMID:26560041 SUPPORT Human Clinical

"T-lymphocyte and NK cell SOCE was grossly abnormal"

Documents the cellular lesion in both T and NK cells of patients, and in a kindred where it was present without overt clinical immunodeficiency, which is why the lesion rather than the clinical severity is what this node records.

PMID:18327260 SUPPORT Model Organism

"Here we show that mouse T cells and fibroblasts lacking the calcium sensor STIM1 had severely impaired store-operated Ca2+ influx"

The mouse knockout reproduces the cellular lesion in both T cells and fibroblasts, supporting STIM1 loss as its cause.

Failure of Calcineurin-NFAT Dependent Transcription

NFAT is heavily phosphorylated and cytoplasmic in resting lymphocytes and enters the nucleus only when dephosphorylated by the calcium/calmodulin dependent phosphatase calcineurin. Without sustained calcium entry calcineurin is not activated, NFAT does not translocate, and the NFAT-dependent transcriptional programme, which includes the cytokine genes and the differentiation programmes of several lymphocyte lineages, is not induced.

calcineurin-NFAT signaling cascade GO:0033173 ↓ DECREASED

Downstream

Impaired T Cell Effector Function Cytokine genes are NFAT targets; their transcription fails.

Reduced Regulatory T and Invariant NKT Cell Numbers Development of the regulatory T and invariant NKT lineages is calcium- and NFAT-dependent, unlike conventional T cell development.

Impaired Activation-Induced T Cell Death Apoptosis of activated T cells is itself calcium-dependent, so the same lesion that blocks activation can also block its termination.

Show evidence (1 reference)

PMID:18327260 SUPPORT Model Organism

"However, T cells lacking either STIM1 or STIM2 had much less cytokine production and nuclear translocation of the transcription factor NFAT."

Connects loss of the STIM calcium sensor to failed NFAT nuclear translocation and the consequent cytokine defect.

Impaired T Cell Effector Function

The defining immunological abnormality. T cells are present in normal numbers and the T cell receptor repertoire is comparable to healthy controls, but the cells fail to proliferate and fail to produce cytokines on stimulation. This is a functional, not a developmental, combined immunodeficiency, which is the point at which STIM1 deficiency separates from the classical T-negative severe combined immunodeficiencies.

T cell CL:0000084

T cell cytokine production GO:0002369 ↓ DECREASED T cell proliferation GO:0042098 ↓ DECREASED

Downstream

Uncontrolled Herpesvirus Infection Antiviral T cell populations are generated but are functionally insufficient to control chronic herpesvirus infection.

Combined immunodeficiency The clinical immunodeficiency is the consequence of the lymphocyte functional defect.

Recurrent infections Failure of T cell effector responses to bacterial, viral and fungal pathogens.

Impaired Antigen-Specific Antibody Response The humoral defect is attributed to failed CD4 T cell help rather than to a B cell-intrinsic requirement for calcium entry.

Show evidence (2 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"A more consistent feature of all ORAI1- and STIM1-deficient T cells is a severe defect in the production of cytokines by CD4+ and CD8+ T cells, including production of IL-2, IL-4, IL-10, IFN-gamma, TNF-alpha, and IL-17A."

The review's synthesis across the published patients, stating the cytokine production defect that defines this node.

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"The distribution of CD4+ and CD8+ T cells, CD16+CD56+ NK cells, and CD19+ or CD20+ B cells in ORAI1- and STIM1-deficient patients is normal."

Establishes the normal lymphocyte counts that make this a defect of function rather than of development.

Impaired Antigen-Specific Antibody Response

Humoral immunity is impaired in these patients, and the review attributes it to the impaired CD4 T cell function above rather than to a B cell-intrinsic lesion. The mouse work supports that reading: deleting both STIM paralogs in B cells alone leaves antigen-specific antibody responses, affinity maturation and germinal centre B cell numbers normal. This is the arm that immunoglobulin replacement substitutes for, and it is why the disease is combined rather than purely cellular.

B cell CL:0000236

immunoglobulin production GO:0002377 ↓ DECREASED

Show evidence (2 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"Taken together, it is likely that impaired CD4+ T cell function in ORAI1- and STIM1-deficient patients contributes to their compromised humoral immunity."

States both the humoral defect and the attribution to T cell help, which is why this node hangs off the T cell effector node.

PMID:26469693 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism

"By contrast, these Stim1fl/flStim2fl/flMb1-Cre mice showed normal primary and memory antigen-specific antibody responses, normal affinity maturation and had similar numbers of germinal center B cells compared to wild type mice suggesting that SOCE is not required for humoral immunity."

The B cell-restricted double knockout has intact antibody responses, which is the negative result that makes the defect T cell-dependent rather than B cell-intrinsic. Graded INDIRECT because it supports the node's attribution by excluding the alternative.

Impaired NK Cell Cytotoxic Function

Patient NK cells show defective granule exocytosis and reduced interferon-gamma production against tumour targets. This arm is independent of the T cell arm and was demonstrated in a kindred without overt clinical immunodeficiency, so it is a cellular defect that does not by itself determine the clinical picture. It contributes to the failure to control herpesvirus infection and plausibly to the herpesvirus-driven malignancy.

natural killer cell CL:0000623

natural killer cell mediated cytotoxicity GO:0042267 ↓ DECREASED

Downstream

Uncontrolled Herpesvirus Infection Impaired NK cytotoxicity is a proposed contributor to the failure to contain chronic CMV and EBV infection.

Show evidence (1 reference)

PMID:26560041 SUPPORT Human Clinical

"The defect in NK cell SOCE was associated with impaired NK cell effector function, as shown by assays of granule exocytosis and intracellular IFN-gamma production in response to K562 tumor cells"

Reports the NK effector defect and the two assays behind it.

Reduced Regulatory T and Invariant NKT Cell Numbers

Regulatory T cells and invariant NKT cells are the only lymphocyte populations consistently reduced in CRAC channelopathy; every other subset is present in normal numbers. In one patient FOXP3-positive regulatory T cells were present but phenotypically abnormal while retaining normal suppressive function in vitro, so the deficit is better described as reduced and abnormal than as absent. This is the node the autoimmunity and the impaired antigen-specific antibody response are attributed to.

regulatory T cell CL:0000815 invariant natural killer T cell CL:0000921

regulatory T cell differentiation GO:0045066 ↓ DECREASED NK T cell differentiation GO:0001865 ↓ DECREASED

Animal models

T cell-specific Stim1 Stim2 double knockout mouse Mouse partially recapitulates Reproduces the selective loss of regulatory T cells, but only when both STIM paralogs are deleted.

Downstream

Loss of Peripheral Immune Tolerance Reduced regulatory T cell numbers remove the dominant mechanism maintaining tolerance to self antigens.

Show evidence (2 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"Reduced numbers of lymphocyte populations in patients are limited to Foxp3+ Treg cells and iNKT cells, which likely account for some of the observed immune dysregulation, such as autoimmunity and impaired production of antigen-specific antibodies"

States both the restriction of the numerical deficit to these two populations and the attribution of the immune dysregulation to it.

PMID:22190180 SUPPORT INDIRECT Human Clinical

"FOXP3-positive regulatory T (Treg) cells were present but showed an abnormal phenotype."

Qualifies the deficit: in this patient regulatory T cells were present and phenotypically abnormal rather than absent. Graded INDIRECT because it bears on the node by restricting what the numerical claim can mean rather than by asserting the reduction.

Impaired Activation-Induced T Cell Death

Apoptosis of activated T cells terminates an immune response, and it is calcium-dependent. It was reported impaired in one STIM1-deficient patient and normal in two others, so the evidence is mixed. Where it is impaired it is the proposed explanation for the lymphoproliferation, which is otherwise paradoxical in a disease of failed lymphocyte activation.

T cell CL:0000084

activation-induced cell death of T cells GO:0006924 ↓ DECREASED

Downstream

Lymphoproliferation Failure to delete activated T cells permits their accumulation.

Show evidence (1 reference)

PMID:26469693 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Impaired T cell apoptosis likely contributes to the lymphoproliferative phenotype of ORAI1- and STIM1-deficient patients."

The review's own hedged attribution of the lymphoproliferation to impaired T cell apoptosis. Graded INDIRECT because the review states it as a likely contribution rather than a demonstrated mechanism, and the underlying patient data disagree between reports.

Loss of Peripheral Immune Tolerance

Autoimmunity in STIM1 deficiency is mild and largely confined to autoimmune cytopenias, unlike the multi-organ autoimmunity of regulatory T cell deficiency in IPEX. The review attributes that restriction to residual regulatory T cells with normal suppressive function, and to the fact that effector T cell function is also impaired, so the autoreactive cells that escape tolerance are themselves poorly functional. Autoimmunity is commoner here than in the sibling disease ORAI1 deficiency, and whether that difference is real is unsettled. The review that reports it also cautions that the ORAI1 patients are few and died early, so they may simply not have lived long enough to develop what STIM1-deficient patients develop. Both readings are recorded rather than one being chosen.

Downstream

Autoimmune hemolytic anemia Coombs-positive autoimmune haemolytic anaemia, usually in the first year of life.

Autoimmune thrombocytopenia Immune thrombocytopenia, in most patients accompanying the haemolytic anaemia.

Show evidence (2 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"A more likely explanation for the patients' autoimmunity is the reduced frequency of CD25+ FOXP3+ Treg cells found in the blood of several STIM1-deficient patients"

The review's attribution of the autoimmunity to the reduced frequency of regulatory T cells, which is the claim this node makes.

PMID:26469693 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Given the small numbers of patients with LoF mutations and their early mortality, it is difficult to say for certain if autoimmunity really is less likely in ORAI1-deficient patients, or if they would develop disease if they did not succumb to immunodeficiency or were treated by HSCT."

The review's own caution about the ORAI1-versus-STIM1 autoimmunity difference this node records. Graded INDIRECT because it bears on the node by limiting what the comparison can be read to mean rather than by asserting the loss of tolerance itself.

Lymphoproliferation

Hepatosplenomegaly and lymphadenopathy from accumulation of lymphocytes, with severe T cell tissue infiltrates in the most severe reported case. This is one of the two features that distinguish STIM1 deficiency from ORAI1 deficiency, and it is the target of the rapamycin treatment reported in 2024.

T cell CL:0000084

Downstream

Lymphadenopathy Lymph node enlargement from lymphocyte accumulation.

Hepatosplenomegaly Liver and spleen enlargement from lymphocyte accumulation and infiltration.

Show evidence (2 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"Lymphoproliferation is a common feature of patients with LoF mutations in STIM1"

States that lymphoproliferation is common in loss-of-function STIM1 disease, which is what this node asserts.

PMID:38578569 SUPPORT Human Clinical

"Lymphoproliferation was associated with severe T-cell infiltrates."

Documents the tissue correlate of the lymphoproliferation in a patient with complete loss of STIM1 protein.

Uncontrolled Herpesvirus Infection

Chronic CMV and EBV infection despite the presence of antiviral T cell populations that proliferate to viral antigen and show normal cytotoxicity in vitro, and fatal disseminated HHV-8-driven Kaposi sarcoma in a child whose only other abnormality was the STIM1 genotype. Herpesvirus control is the arm of immunity that fails most conspicuously, and the Kaposi sarcoma case is the evidence that it fails in a T-cell-dependent way.

Downstream

Kaposi's sarcoma HHV-8 infection progressing to disseminated Kaposi sarcoma in the absence of effective T cell control.

Recurrent viral infections Chronic and recurrent viral infection is the clinical expression of the failed antiviral response.

Show evidence (1 reference)

PMID:22190180 SUPPORT Human Clinical

"However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells."

States the failure of herpesvirus control and the two cellular contributions the authors propose for it.

Impaired Skeletal Muscle Calcium Handling

Store-operated calcium entry refills sarcoplasmic reticulum calcium stores during sustained activity, and skeletal muscle needs it: myotubes without functional STIM1 fatigue rapidly, and mice without functional STIM1 die perinatally of a skeletal myopathy. In patients the consequence is a congenital, non-progressive global muscular hypotonia without structural abnormality on biopsy, which is the form the muscle involvement takes in the loss-of-function CRAC channelopathies.

skeletal muscle fiber CL:0008002

skeletal muscle contraction GO:0003009 ↓ DECREASED

Animal models

Stim1 null mouse Mouse recapitulates Reproduces the loss of store-operated calcium entry in muscle and its contractile consequence.

Downstream

Generalized hypotonia Congenital non-progressive global muscular hypotonia.

Muscle weakness Weakness accompanying the hypotonia, reported across the severity range.

Show evidence (2 references)

PMID:18488020 SUPPORT Model Organism

"Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly. Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy."

Establishes that skeletal muscle requires STIM1-dependent SOCE for contractile function, which is the mechanism behind the patients' hypotonia.

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"LoF or null mutations in ORAI1 and STIM1 resulted in congenital, non-progressive muscular hypotonia in all but one patient"

States the human correlate, including that it is congenital and non-progressive, which distinguishes it from the progressive myopathy of the gain-of-function diseases.

Defective Enamel Mineralization

Ameloblasts secrete the enamel matrix and supply the calcium that mineralizes it, and they depend on store-operated calcium entry to do so. In mice lacking STIM1 and STIM2 in enamel cells the enamel is hypomineralized, thinner and mechanically weak, the ameloblasts lose their ruffled border, and the cells show ER stress and mitochondrial dysfunction. In patients the result is a generalized developmental enamel defect, and because the requirement persists after birth the later erupting permanent teeth are affected too, including in patients who survive the immunodeficiency.

ameloblast CL:0000059

enamel mineralization GO:0070166 ↓ DECREASED

Animal models

Ectodermal Stim1 Stim2 double knockout mouse Mouse recapitulates Reproduces the enamel defect and identifies the ameloblast changes and the oxidative and ER stress behind it.

Downstream

Amelogenesis imperfecta Generalized developmental enamel abnormality.

Show evidence (2 references)

PMID:28352661 SUPPORT Model Organism

"Enamel in Stim1/2K14cre mice was hypomineralized with decreased Ca content, mechanically weak, and thinner."

Establishes the mechanism of the enamel defect in an animal model built specifically because the human enamel phenotype had no explanation.

PMID:19420366 SUPPORT Human Clinical

"She also had a defect in enamel dentition, which became apparent in the first years of life."

The human enamel phenotype in the founding kindred, and its early onset.

Sweat Gland Secretory Failure

Eccrine sweat glands develop normally but cannot secrete. SOCE is required to activate the calcium-activated chloride channel ANO1, and without chloride secretion there is no fluid secretion. CRAC channel-deficient patients and mice with ectodermal deletion of Stim1 and Stim2 both fail to sweat, and the clinical consequence is hypohidrosis with heat intolerance.

sweat secretion GO:0160269 ↓ DECREASED

Animal models

Ectodermal Stim1 Stim2 double knockout mouse Mouse recapitulates Reproduces the secretory failure of structurally normal sweat glands, and identifies the calcium-activated chloride channel step.

Downstream

Hypohidrosis Reduced sweating, with heat intolerance at high ambient temperature.

Show evidence (1 reference)

PMID:27721237 SUPPORT Human Clinical

"Here we have shown that CRAC channel-deficient patients and mice with ectodermal tissue-specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development."

Establishes that the failure is secretory rather than developmental, in patients as well as in mice.

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Pathograph

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Phenotypes

Blood 2

Autoimmune hemolytic anemia HP:0001890

Show evidence (2 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"Most of these patients also develop Coombs-positive autoimmune hemolytic anemia (AIHA) and thrombocytopenia in their first year of life."

States both the character of the anaemia and its timing across the published loss-of-function STIM1 patients.

PMID:19420366 SUPPORT Human Clinical

"at 15 months she was found to have autoimmune hemolytic anemia, and at 5 years thrombocytopenia, both of which were treated with glucocorticoids"

The individual clinical course in the founding kindred, including the treatment given.

Autoimmune thrombocytopenia HP:0001973

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"She had a clinical picture similar to that of her older sister, including severe autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatosplenomegaly, partial iris hypoplasia, and muscular hypotonia."

Documents thrombocytopenia as part of the syndrome in a second affected sibling, alongside the other features of the entry.

Cardiovascular 2

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"Lymphadenopathy and hepatosplenomegaly were apparent at 7 months of age"

Documents lymphadenopathy and its age of onset in the index patient.

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"We report on three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition."

Lists hepatosplenomegaly among the defining features of the syndrome in the founding kindred.

Eye 2

Hypoplasia of the iris HP:0007676

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"Currently, at 6 years of age, he has nonprogressive muscular hypotonia and partial iris hypoplasia only."

Documents the iris hypoplasia, and that it is one of the two features remaining after successful transplantation.

Mydriasis HP:0011499

Show evidence (1 reference)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"partial iris hypoplasia and/or mydriasis"

The review's statement of the ocular finding across ORAI1- and STIM1-deficient patients.

Head and Neck 1

Amelogenesis imperfecta HP:0000705

Show evidence (1 reference)

PMID:26560041 SUPPORT Human Clinical

"We investigated a consanguineous family, segregating a novel syndrome of recessive AI and hypohidrosis by using autozygosity mapping and clonal sequencing."

Reports amelogenesis imperfecta, abbreviated AI in this paper, together with hypohidrosis as the presenting syndrome in a STIM1-mutant kindred.

Immune 4

Combined immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"A principal feature of most cases of combined immunodeficiency disease is impaired function of T, B, or natural killer cells, despite their normal development."

The founding report's framing of the disease it is describing, which is the function-not-development distinction this phenotype records.

Recurrent infections HP:0002719

Sequelae: Pneumonia

Show evidence (1 reference)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"ORAI1- and STIM1-deficient patients suffer from recurrent and severe infections with viral, bacterial and fungal pathogens"

The review's statement of the infection phenotype across the published patients.

Recurrent viral infections HP:0004429

Show evidence (1 reference)

PMID:22190180 SUPPORT Human Clinical

"However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections"

Documents chronic herpesvirus infection in a patient with a homozygous STIM1 missense allele.

Pneumonia HP:0002090

Show evidence (1 reference)

PMID:40411647 SUPPORT Human Clinical

"The patient presented with recurrent pneumonia, blood-streaked diarrhea, eczema, muscle weakness, and failure to thrive."

Documents recurrent pneumonia as a presenting feature in a patient with a novel homozygous STIM1 missense allele.

Integument 2

Kaposi's sarcoma HP:0100726

Show evidence (1 reference)

PMID:20876309 SUPPORT Human Clinical

"We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age."

Documents the Kaposi sarcoma and, importantly, that it was the presenting and isolated severe phenotype in this child.

Hypohidrosis HP:0000966

Show evidence (1 reference)

PMID:27721237 SUPPORT Human Clinical

"patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures"

States the sweating phenotype and the heat intolerance that follows from it in CRAC channel-deficient patients.

Musculoskeletal 2

Generalized hypotonia HP:0001290

Course: STABLE

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"Despite normal early cognitive development, the neonatal period of Patient V-1 was conspicuous because of partial iris hypoplasia and nonprogressive global muscular hypotonia"

Documents the hypotonia, its congenital onset and its non-progressive course, which is what `clinical_course: STABLE` records.

Muscle weakness HP:0001324

Show evidence (2 references)

PMID:40411647 SUPPORT Human Clinical

"The patient presented with recurrent pneumonia, blood-streaked diarrhea, eczema, muscle weakness, and failure to thrive."

Lists muscle weakness among the presenting features in a patient with a novel homozygous STIM1 missense allele.

PMID:33733462 SUPPORT Human Clinical

"presenting with muscle weakness, hyperlaxity, elastic skin, tooth abnormalities, dysmorphic facies, hypoplastic patellae and history of respiratory infections"

The same feature in the protein-null siblings whose presentation was otherwise unlike the classical immunodeficiency picture, which is the breadth this entry's notes record.

🧬

Genetic Associations

STIM1

Gene: STIM1 hgnc:11386 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:19420366 SUPPORT Human Clinical

"Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx."

The gene-disease assertion, from the report that established it.

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and..."

Supports the scope statement in this record: the same gene carries a distinct gain-of-function disease spectrum that this entry excludes.

💊

Medical Actions

Hematopoietic Stem Cell Transplantation

Action: haematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Allogeneic haematopoietic stem cell transplantation is what the severe immunodeficiency requires, and it is curative for the immunological arm. It does not correct the non-haematopoietic arms: the transplanted survivor in the founding kindred retained his hypotonia and iris hypoplasia, and the permanent dentition of survivors still requires extensive dental work. Outcomes in the published cohort are mixed, with deaths from transplant complications and from comorbid conditions.

Mechanism Target:

Impaired T Cell Effector Function — Replaces the patient's haematopoietic system, and with it the STIM1-deficient lymphocytes.

Show evidence (3 references)

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"The clinical phenotype of patients with null or LoF mutations in ORAI1 or STIM1 is dominated by life-threatening immunodeficiency that typically manifests in the first year of life and requires hematopoietic stem cell therapy (HSCT) to control the disease."

States that transplantation is what controls the disease, which is the basis for recording it as the definitive treatment.

PMID:19420366 SUPPORT Human Clinical

"Currently, at 6 years of age, he has nonprogressive muscular hypotonia and partial iris hypoplasia only."

Documents the limit of what transplantation achieves: the immunological and autoimmune features resolved, the muscle and eye features did not.

PMID:26469693 SUPPORT REVIEW SYNTHESIS Human Clinical

"Four patients survived after HSCT, 3 died from comorbid conditions or failed HSCT, and 3 survived without HSCT, presumably due to hypomorphic mutations"

The outcome tally across the published CRAC channelopathy cohort, which is why this record does not describe transplantation as uniformly successful.

Sirolimus

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Platform: Small molecule

The mTOR inhibitor rapamycin was used in a patient with complete loss of STIM1 protein and severe lymphoproliferation; it controlled the lymphoproliferation and improved T cell activation and proliferation capacity. This is a single reported patient, and the authors present it as a first use in this disorder rather than as established practice.

Mechanism Target:

Lymphoproliferation — Directed at the lymphoproliferative arm rather than at the underlying calcium signalling defect.

Show evidence (2 references)

PMID:38578569 SUPPORT Human Clinical

"Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities"

Reports the clinical and immunological response in the single treated patient.

PMID:38578569 SUPPORT Human Clinical

"reveals for the first time the potential therapeutic utility of rapamycin for this disorder"

The authors' own framing, which is why this record describes the evidence as a single reported use rather than established practice.

Glucocorticoid Therapy for Autoimmune Cytopenias

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

The autoimmune haemolytic anaemia and thrombocytopenia were treated with glucocorticoids in the founding kindred. This is symptomatic treatment of the autoimmune arm, not disease-modifying therapy.

Mechanism Target:

Loss of Peripheral Immune Tolerance — Suppresses the autoimmune effector response rather than restoring tolerance.

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"at 15 months she was found to have autoimmune hemolytic anemia, and at 5 years thrombocytopenia, both of which were treated with glucocorticoids"

Documents glucocorticoid treatment of both autoimmune cytopenias.

Immunoglobulin Replacement

Action: Pharmacotherapy NCIT:C15986

Agent: human immunoglobulin G NCIT:C80829

Platform: Protein replacement

Intravenous immunoglobulin was given for the humoral defect and was stopped after successful transplantation in the founding kindred, which is itself evidence that the humoral arm is corrected by transplantation.

Mechanism Target:

Impaired Antigen-Specific Antibody Response — Substitutes for the antibody response that fails downstream of impaired T cell help, rather than acting on the calcium signalling defect.

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

"Patient V-7 survived after hematopoietic stem-cell transplantation (with a healthy, HLA-identical sister as donor) performed at 15 months of age, and intravenous immune globulin was stopped."

Documents immunoglobulin replacement and that it was discontinued once the transplant had reconstituted the immune system.

🔬

Diagnosis

Store-operated calcium entry measurement

Functional demonstration of impaired or absent store-operated calcium entry in patient T cells or fibroblasts, by calcium imaging after store depletion. This is the assay that defines the CRAC channelopathies as a group, and it does not distinguish STIM1 from ORAI1 deficiency: the gene test does that.

Show evidence (1 reference)

PMID:38977117 SUPPORT Human Clinical

"Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function."

Describes the functional assay and what a positive result establishes, in a patient diagnosed by this route.

STIM1 sequencing

Molecular confirmation by exome sequencing, a primary immunodeficiency gene panel, or targeted STIM1 sequencing. In a patient with combined immunodeficiency plus hypohidrosis and enamel defects, STIM1 and ORAI1 are the two genes to sequence together, since they produce a nearly superimposable syndrome and only the genotype separates them.

Show evidence (1 reference)

PMID:33733462 SUPPORT Human Clinical

"Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1"

Exome sequencing as the route to molecular diagnosis in a kindred whose presentation was not the classical immunodeficiency picture.

📊

Prevalence

Worldwide, published cases

Cases In Literature Ultra Rare

A small number of kindreds have been published since the gene was identified in 2009. No incidence or prevalence estimate exists, and none is computable from a cohort of this size.

Show evidence (1 reference)

PMID:19420366 SUPPORT Human Clinical

The founding report describes three siblings from a single kindred. This is a study case count, not a population rate.

🐁

Animal Models

Stim1 null mouse

Mice lacking functional STIM1 die perinatally of a skeletal myopathy, and their myotubes show no store-operated calcium entry and fatigue rapidly. The model establishes the muscle arm of the human disease. Its perinatal lethality is itself a species difference: human patients with complete loss of STIM1 protein survive with a non-progressive hypotonia.

Species

Mouse

Genotype

Stim1 loss-of-function (null)

Publication

PMID:18488020

Pathograph links

Impaired Skeletal Muscle Calcium Handling recapitulates fidelity: moderate observes: cellular Reproduces the loss of store-operated calcium entry in muscle and its contractile consequence.

Limitations: The mouse dies perinatally of myopathy whereas the human phenotype is a survivable non-progressive hypotonia, so the model overstates the severity of the muscle arm. The measurement is made in myotubes, which is a cellular readout for a tissue-level node.

Divergences from the human mechanism

species mismatch qualifying

Perinatal lethality from skeletal myopathy has no counterpart in patients with protein-null STIM1 genotypes, who survive with non-progressive hypotonia. The direction of the difference matters: the model is more severe than the disease.

scale extrapolation qualifying

Store-operated calcium entry and fatigue are measured in cultured myotubes, while the node is the tissue-level calcium-handling defect of skeletal muscle in vivo.

Readouts

Store-operated calcium entry in myotubes

Direction: ABOLISHED

Interpretation: The cellular lesion in muscle, in the same direction as in patient cells.

Show evidence (1 reference)

PMID:18488020 SUPPORT Model Organism

"Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly."

Reports the abolished store-operated calcium entry and the contractile consequence.

Show evidence (1 reference)

PMID:18488020 SUPPORT Model Organism

"Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy."

Establishes that STIM1 loss produces a skeletal myopathy in vivo, which is what makes this model informative for the muscle node.

T cell-specific Stim1 Stim2 double knockout mouse

T cell-specific deletion of both STIM calcium sensors reproduces the two features that distinguish human STIM1 deficiency from ORAI1 deficiency, namely lymphoproliferation and a selective reduction in regulatory T cell numbers. Note the model deletes both STIM1 and STIM2: the review records that regulatory and NKT cells are absent only in the double-deficient mouse and not in the STIM1 single knockout, which is why the human reduction is partial rather than absolute.

Species

Mouse

Genotype

Stim1 and Stim2 conditional deletion in T cells (Cd4-Cre)

Publication

PMID:18327260

Pathograph links

Reduced Regulatory T and Invariant NKT Cell Numbers partially recapitulates fidelity: moderate observes: cellular Reproduces the selective loss of regulatory T cells, but only when both STIM paralogs are deleted.

Limitations: Human disease is STIM1-only, and the mouse requires additional Stim2 deletion to abolish these populations, so the genotype is more severe than the human genotype. The deletion is also T cell-restricted, so non-immune arms of the disease are outside the model.

Divergences from the human mechanism

species mismatch qualifying

The model deletes Stim1 and Stim2 together, where patients lose STIM1 alone and retain STIM2. Residual STIM2-dependent calcium entry is the stated reason the human deficit in these populations is partial.

boundary omission immaterial

Deletion is restricted to T cells, so the muscle, enamel and sweat gland arms of the disease are not in the model. That does not bear on this link, which concerns a T cell population.

Readouts

Regulatory T cell numbers

Direction: DECREASED

Interpretation: The same direction as the reduced regulatory T cell frequency in patients.

Show evidence (1 reference)

PMID:18327260 SUPPORT Model Organism

"T cell-specific ablation of both STIM1 and STIM2 resulted in a notable lymphoproliferative phenotype and a selective decrease in regulatory T cell numbers."

Reports the selective reduction in regulatory T cells in the double knockout.

Show evidence (1 reference)

PMID:18327260 SUPPORT Model Organism

"We conclude that both STIM1 and STIM2 promote store-operated Ca2+ entry into T cells and fibroblasts and that STIM proteins are required for the development and function of regulatory T cells."

States the requirement for STIM proteins in regulatory T cell development, which is the claim this link rests on.

Ectodermal Stim1 Stim2 double knockout mouse

Deletion of both STIM sensors in ectodermal tissue abolishes sweating despite normal sweat gland development, and produces hypomineralized, thin, mechanically weak enamel with abnormal ameloblast morphology. The model was built because the human enamel and sweating phenotypes had no mechanistic explanation, and it supplies both.

Species

Mouse

Genotype

Stim1 and Stim2 conditional deletion in ectodermal tissue (K14-Cre)

Publication

PMID:27721237

Pathograph links

Sweat Gland Secretory Failure recapitulates fidelity: high observes: tissue Reproduces the secretory failure of structurally normal sweat glands, and identifies the calcium-activated chloride channel step.

Limitations: As with the other conditional models, both STIM paralogs are deleted where patients lose only STIM1.

Divergences from the human mechanism

species mismatch qualifying

Stim1 and Stim2 are deleted together, a more complete loss of store-operated calcium entry than the human STIM1-only genotype.

Readouts

Sweat production

Direction: ABOLISHED

Interpretation: Matches the hypohidrosis of patients, with glands present.

Show evidence (1 reference)

PMID:27721237 SUPPORT Model Organism

"SOCE was absent in agonist-stimulated sweat glands from Orai1K14Cre and Stim1/2K14Cre mice and human sweat gland cells lacking ORAI1 or STIM1 expression."

Reports the abolished response in the model and, in parallel, in human cells.

Defective Enamel Mineralization recapitulates fidelity: high observes: tissue Reproduces the enamel defect and identifies the ameloblast changes and the oxidative and ER stress behind it.

Limitations: Both STIM paralogs are deleted, and the mechanistic chain from ameloblast ER stress to hypomineralization is established in the mouse rather than in patient tissue.

Divergences from the human mechanism

species mismatch qualifying

Stim1 and Stim2 are deleted together, where patients retain STIM2.

Readouts

Enamel mineral content

Direction: DECREASED

Interpretation: The structural correlate of the patients' amelogenesis imperfecta.

Show evidence (1 reference)

PMID:28352661 SUPPORT Model Organism

"Enamel in Stim1/2K14cre mice was hypomineralized with decreased Ca content, mechanically weak, and thinner."

Reports the reduced mineral content and the mechanical consequence.

Show evidence (1 reference)

PMID:28352661 SUPPORT Model Organism

"The cause of these enamel defects has remained unclear given a lack of animal models."

States why this model exists: the human enamel defect had no mechanistic account before it, which is what makes it informative for this node.

{ }

Source YAML

click to show

name: STIM1 Deficiency
creation_date: "2026-09-29T21:00:00Z"
category: Mendelian
synonyms:
- combined immunodeficiency due to STIM1 deficiency
- CID due to STIM1 deficiency
- immunodeficiency 10
- IMD10
- STIM1 deficiency
- CRAC channelopathy due to STIM1 deficiency
- stromal interaction molecule 1 deficiency
disease_term:
  preferred_term: combined immunodeficiency due to STIM1 deficiency
  term:
    id: MONDO:0013008
    label: combined immunodeficiency due to STIM1 deficiency
parents:
- Primary Immunodeficiency
- Combined Immunodeficiency
- Channelopathy
classifications:
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      A combined immunodeficiency accompanied by non-immune features, namely
      congenital muscular hypotonia and ectodermal dysplasia with defective
      enamel and hypohidrosis. That is the shape of the IUIS syndromic-CID
      group, and it is the committee's own placement: the STIM1 row sits in
      the Calcium Channel Defects section of the syndromic-CID table, beside
      the ORAI1 row that the sibling entry cites.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      directness: DIRECT
      snippet: "STIM1 deficiency STIM1 AR 605921"
      explanation: >-
        The STIM1 deficiency row of the IUIS table, naming the gene, autosomal
        recessive inheritance and the OMIM gene number. The row sits in
        Table 2, "Combined immunodeficiencies with associated or syndromic
        features", section 8 Calcium Channel Defects, so the syndromic-CID
        assignment is the committee's placement rather than an inference from
        the phenotype. Graded OTHER because the source is an expert-committee
        classification document rather than a study.
description: >
  STIM1 deficiency is an autosomal recessive CRAC (calcium release-activated
  calcium) channelopathy. STIM1 is the endoplasmic reticulum calcium sensor
  that detects store depletion and gates ORAI1, the pore-forming subunit of
  the plasma membrane CRAC channel. Biallelic loss-of-function STIM1 variants
  abolish store-operated calcium entry (SOCE), so calcineurin is not activated
  and the NFAT-dependent transcriptional programme is not induced. Lymphocyte
  numbers and development are essentially normal; what fails is lymphocyte
  function, which is why the disease is a combined immunodeficiency rather
  than a classical T-negative severe combined immunodeficiency.

  The clinical syndrome combines life-threatening infection in the first years
  of life, including chronic herpesvirus infection and herpesvirus-driven
  malignancy, with congenital non-progressive muscular hypotonia, ectodermal
  dysplasia with defective dental enamel and hypohidrosis, and partial iris
  hypoplasia or mydriasis. Two features distinguish it from its sibling
  disease ORAI1 deficiency: lymphoproliferation with hepatosplenomegaly and
  lymphadenopathy is common, and autoimmune cytopenias, usually
  Coombs-positive haemolytic anaemia and thrombocytopenia in the first year of
  life, are usual rather than exceptional. Both track with reduced numbers of
  FOXP3-positive regulatory T cells and invariant natural killer T cells,
  which are the only lymphocyte populations consistently reduced.

  Allogeneic haematopoietic stem cell transplantation addresses the
  immunological arm and is what the severe cases require; the myopathic,
  ectodermal and ocular arms are cell-intrinsic to non-haematopoietic tissue
  and persist after transplantation. The disease is ultra-rare, and the
  published phenotype is wide at the mild end: two cousins homozygous for a
  missense EF-hand allele had grossly abnormal lymphocyte calcium entry
  without overt clinical immunodeficiency, and two siblings with a frameshift
  allele abolishing STIM1 protein presented with a connective-tissue and
  skeletal picture rather than with severe immune disease.
notes: >
  Ultra-rare. The published cohort is a small number of kindreds: the founding
  family with a homozygous nonsense allele in STIM1 exon 3 (Picard et al.,
  NEJM 2009), two siblings homozygous for p.R429C (Fuchs et al., 2012), a
  child with a homozygous splice-site allele who died of Kaposi sarcoma (Byun
  et al., 2010), two cousins homozygous for the EF-hand allele p.L74P (Parry
  et al., 2016), two siblings homozygous for c.685delT (Salvi et al., 2021),
  and further single patients since. Counts in this entry are therefore counts
  of kindreds or patients, never frequencies, and `frequency` is deliberately
  left unset throughout.

  The disease is one of lymphocyte function, not lymphocyte development. T, B
  and NK cell numbers are normal, and the defect appears on stimulation. That
  is what separates it from the classical T-B-NK- severe combined
  immunodeficiencies its SCID-like presentation invites comparison with, and
  it is why the pathograph routes through cytokine transcription rather than
  through a lymphopoiesis node.

  The phenotype is wider at the mild end than the SCID-like description
  suggests, and this matters for reading a new patient. Two cousins homozygous
  for p.L74P had amelogenesis imperfecta and hypohidrosis with grossly
  abnormal lymphocyte and NK cell SOCE but no overt clinical immunodeficiency,
  and two siblings with a frameshift allele abolishing STIM1 protein entirely
  presented with a connective-tissue and skeletal picture rather than with
  immune disease. So neither the allele class nor the absence of protein
  predicts immunological severity, and the nodes below record the mechanism
  rather than a uniform clinical outcome.

  The sibling disease is ORAI1 deficiency (MONDO:0013007), curated as
  `kb/disorders/ORAI1_Deficiency.yaml`. Both sit under `combined
  immunodeficiency due to CRAC channel dysfunction` (MONDO:0015695), and the
  2015 review calls the two phenotypes almost identical, naming
  lymphoproliferation and autoimmune cytopenias as the apparent difference
  while cautioning that the small patient numbers and early mortality in
  ORAI1 deficiency may be what produces it. That caution is recorded on the
  `Loss of Peripheral Immune Tolerance` node rather than resolved here. No
  `has_subtypes` relationship is asserted between the two: they are separate genes and separate MONDO
  concepts, and the right structure for the pair is a future grouping.

  STIM1 is a two-faced gene, and this entry is only one of its faces.
  Autosomal dominant gain-of-function STIM1 variants constitutively activate
  the CRAC channel and cause tubular aggregate myopathy, York platelet
  syndrome and Stormorken syndrome. Those are not STIM1 deficiency and are not
  curated here. The distinction is practical: a literature search on STIM1
  returns both, and the myopathy in the gain-of-function diseases is a
  different lesion from the congenital hypotonia described below, despite both
  being muscle. Miosis in Stormorken syndrome and iris hypoplasia or mydriasis
  here are likewise different eye findings.

  `channelopathy_category` is deliberately unset, for the same reason the
  ORAI1 entry gives: `ChannelopathyOrganSystemEnum` offers cardiac, skeletal
  muscle, neurological and epithelial, and none of them names an immune
  channelopathy, which is what this disease principally is. The enum needs an
  immune value rather than this entry needing a wrong one.

  No `conforms_to` was declared. The module directory was searched and none
  matches: this is a channel-gated transcription-factor activation failure,
  not an inflammatory, fibrotic or degeneration chain. If a
  calcium-signalling-failure module is ever created, this entry and ORAI1
  deficiency are its first two conformers.

  A splice-correcting antisense oligonucleotide has been reported to improve
  STIM1 splicing in cells from a patient with a splice-site allele. It is
  recorded here rather than in `treatments:` because it was tested in patient
  cells only, has been given to nobody, and would apply only to
  splice-altering genotypes. Note also that the CRAC-channel modulators in
  development are blockers, aimed at gain-of-function and inflammatory
  indications; a blocker is the wrong direction for a loss-of-function
  disease.

  Deep-research provenance. An OpenScientist run
  (`research/STIM1_Deficiency-deep-research-openscientist.md`) is committed
  alongside this entry. `just preflight-dr` scores it WARN, on the ORAI1
  mention count rather than on anything wrong: STIM1 is mentioned 98 times and
  ORAI1 32, and ORAI1 is this disease's own partner protein, which is the
  ambiguity the check's own message says a mention count cannot resolve. The
  report contributed the diagnostic workup and the antisense oligonucleotide
  note above. Every quote used here was re-verified against the fetched
  reference cache rather than taken from the report.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Reported patients are homozygous for loss-of-function STIM1 alleles, in
    several instances from consanguineous kindreds. Heterozygous parents and
    siblings are clinically unaffected.
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx."
    explanation: >
      Establishes homozygosity for a single STIM1 nonsense allele in the
      founding kindred, that is, autosomal recessive inheritance.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A small number of kindreds have been published since the gene was
    identified in 2009. No incidence or prevalence estimate exists, and none
    is computable from a cohort of this size.
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition."
    explanation: >-
      The founding report describes three siblings from a single kindred. This
      is a study case count, not a population rate.
pathophysiology:
- name: Biallelic Loss-of-Function STIM1 Variants
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: calcium channel regulator activity
    term:
      id: GO:0005246
      label: calcium channel regulator activity
    modifier: LOSS_OF_FUNCTION
  description: >
    Homozygous STIM1 variants. Reported alleles include a nonsense change in
    exon 3, a splice-site change, the frameshift c.685delT, and the missense
    alleles p.L74P (EF-hand), p.L195P and p.R429C (coiled-coil domain 3).
    Nonsense, splice and frameshift alleles abolish STIM1 protein outright;
    the missense alleles leave protein expressed but unable to sense store
    depletion or to gate ORAI1, so null and functionally-null genotypes
    converge on the same cellular lesion.
  genes:
  - preferred_term: STIM1
    term:
      id: hgnc:11386
      label: STIM1
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    description: >-
      Germline biallelic STIM1 alleles. Both protein-abolishing (nonsense,
      splice-site, frameshift) and expression-preserving but
      function-abolishing (missense) mechanisms are represented.
    allelic_events:
    - NONSENSE_VARIANT
    - MISSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    - SPLICE_SITE_VARIANT
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx."
    explanation: >
      The founding allele, and the statement that it removes both STIM1
      protein and calcium influx, which is what makes loss of function the
      disease mechanism.
  - reference: PMID:22190180
    reference_title: "Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two patients with a homozygous R429C point mutation in STIM1 completely abolishing store-operated calcium entry in T cells."
    explanation: >
      Extends the allelic spectrum to a missense allele that abolishes SOCE,
      establishing that an expressed but non-functional protein produces the
      same cellular lesion.
  - reference: PMID:33733462
    reference_title: "A novel bi-allelic loss-of-function mutation in STIM1 expands the phenotype of STIM1-related diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1"
    explanation: >
      A frameshift allele, c.685delT, abolishing STIM1 protein, which is the
      second protein-null mechanism in the allelic spectrum. The quote stops
      before the variant nomenclature because the reference validator strips
      bracketed spans before matching, so the protein-level description in
      square brackets cannot be quoted without a `literal_bracket_patterns`
      entry in `conf/reference_validator_config.yaml`. The item below carries
      the complete-loss claim from the same abstract.
  - reference: PMID:33733462
    reference_title: "A novel bi-allelic loss-of-function mutation in STIM1 expands the phenotype of STIM1-related diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In particular, we confirmed that the complete loss of STIM1 function is not always associated with severe immune disorders."
    explanation: >
      Records the limit on what this node's loss-of-function claim implies
      clinically: a protein-null genotype does not guarantee severe immune
      disease.
  downstream:
  - target: Loss of ER Calcium Store Sensing and CRAC Channel Gating
    description: >-
      Absent or non-functional STIM1 cannot detect endoplasmic reticulum
      calcium depletion or gate ORAI1.
    causal_link_type: DIRECT

- name: Loss of ER Calcium Store Sensing and CRAC Channel Gating
  biological_scale: MOLECULAR
  description: >
    STIM1 is the endoplasmic reticulum calcium sensor of the CRAC channel
    complex. Its luminal EF-hand binds ER calcium; on store depletion STIM1
    oligomerizes, translocates to ER-plasma membrane junctions and gates
    ORAI1 through its cytoplasmic coiled-coil domains. Without functional
    STIM1 there is no signal from the depleted store to the pore, so the CRAC
    channel is never opened even though ORAI1 itself is intact. That the
    lesion is STIM1 and not a correlated defect is established by rescue:
    expressing wild-type STIM1 in patient cells restores calcium influx.
  molecular_functions:
  - preferred_term: calcium channel regulator activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0005246
      label: calcium channel regulator activity
  evidence:
  - reference: PMID:20876309
    reference_title: "Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "STIM1 mRNA splicing, protein production, and Ca(2+) influx were completely abolished in EBV-transformed B cell lines from the patient, but were rescued by the expression of wild-type STIM1."
    explanation: >
      The rescue result establishes that loss of STIM1 is what removes calcium
      influx in patient cells, rather than a correlated abnormality.
  downstream:
  - target: Abolished Store-Operated Calcium Entry
    description: >-
      With no gating signal reaching ORAI1, store depletion no longer produces
      sustained calcium influx.
    causal_link_type: DIRECT

- name: Abolished Store-Operated Calcium Entry
  biological_scale: CELLULAR
  description: >
    Store-operated calcium entry is the dominant sustained calcium influx
    pathway in lymphocytes, and it is also required in skeletal muscle,
    ameloblasts and eccrine sweat gland cells. Its loss is demonstrable in
    patient T cells, NK cells, B cell lines and fibroblasts, and is the single
    cellular lesion from which every arm of the disease follows. STIM1 is
    near-ubiquitously expressed, so the lesion is present in far more tissues
    than are clinically affected: the restriction of the phenotype reflects
    where SOCE is non-redundant, not where STIM1 is expressed.
  biological_processes:
  - preferred_term: store-operated calcium entry
    modifier: DECREASED
    term:
      id: GO:0002115
      label: store-operated calcium entry
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:26560041
    reference_title: "A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "T-lymphocyte and NK cell SOCE was grossly abnormal"
    explanation: >
      Documents the cellular lesion in both T and NK cells of patients, and in
      a kindred where it was present without overt clinical immunodeficiency,
      which is why the lesion rather than the clinical severity is what this
      node records.
  - reference: PMID:18327260
    reference_title: "Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that mouse T cells and fibroblasts lacking the calcium sensor STIM1 had severely impaired store-operated Ca2+ influx"
    explanation: >
      The mouse knockout reproduces the cellular lesion in both T cells and
      fibroblasts, supporting STIM1 loss as its cause.
  downstream:
  - target: Failure of Calcineurin-NFAT Dependent Transcription
    description: >-
      Sustained cytosolic calcium is required to activate calcineurin; without
      it NFAT remains phosphorylated and cytoplasmic.
    causal_link_type: DIRECT
  - target: Impaired NK Cell Cytotoxic Function
    description: >-
      NK cell granule exocytosis and interferon-gamma production are
      calcium-dependent and fail in patient cells.
    causal_link_type: DIRECT
  - target: Impaired Skeletal Muscle Calcium Handling
    description: >-
      Loss of SOCE in skeletal muscle fibres, where it refills sarcoplasmic
      reticulum calcium stores during sustained activity.
    causal_link_type: DIRECT
  - target: Defective Enamel Mineralization
    description: >-
      Ameloblasts depend on store-operated calcium influx for the calcium
      handling and secretory function that mineralize enamel.
    causal_link_type: DIRECT
  - target: Sweat Gland Secretory Failure
    description: >-
      Eccrine sweat gland secretion requires SOCE to activate the
      calcium-activated chloride channel that drives fluid secretion.
    causal_link_type: DIRECT
  - target: Mydriasis
    description: >-
      Mydriasis is reported alongside the iris hypoplasia, by the same route
      and with the same uncertainty about the intermediate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Calcium handling in iris smooth muscle, proposed by analogy with the skeletal muscle hypotonia but not demonstrated
  - target: Hypoplasia of the iris
    description: >-
      Partial iris hypoplasia and mydriasis are reported in several patients.
      The route is left unspecified: the 2015 review reads them as a further
      sign of the muscular hypotonia, which would place them downstream of
      smooth rather than skeletal muscle calcium handling, and no study has
      identified the intermediate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Calcium handling in iris smooth muscle, proposed by analogy with the skeletal muscle hypotonia but not demonstrated

- name: Failure of Calcineurin-NFAT Dependent Transcription
  biological_scale: CELLULAR
  description: >
    NFAT is heavily phosphorylated and cytoplasmic in resting lymphocytes and
    enters the nucleus only when dephosphorylated by the calcium/calmodulin
    dependent phosphatase calcineurin. Without sustained calcium entry
    calcineurin is not activated, NFAT does not translocate, and the
    NFAT-dependent transcriptional programme, which includes the cytokine
    genes and the differentiation programmes of several lymphocyte lineages,
    is not induced.
  biological_processes:
  - preferred_term: calcineurin-NFAT signaling cascade
    modifier: DECREASED
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
  evidence:
  - reference: PMID:18327260
    reference_title: "Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, T cells lacking either STIM1 or STIM2 had much less cytokine production and nuclear translocation of the transcription factor NFAT."
    explanation: >
      Connects loss of the STIM calcium sensor to failed NFAT nuclear
      translocation and the consequent cytokine defect.
  downstream:
  - target: Impaired T Cell Effector Function
    description: >-
      Cytokine genes are NFAT targets; their transcription fails.
    causal_link_type: DIRECT
  - target: Reduced Regulatory T and Invariant NKT Cell Numbers
    description: >-
      Development of the regulatory T and invariant NKT lineages is
      calcium- and NFAT-dependent, unlike conventional T cell development.
    causal_link_type: DIRECT
  - target: Impaired Activation-Induced T Cell Death
    description: >-
      Apoptosis of activated T cells is itself calcium-dependent, so the same
      lesion that blocks activation can also block its termination.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Calcium-dependent apoptotic signalling in activated T cells, reported impaired in one patient and normal in two others

- name: Impaired T Cell Effector Function
  biological_scale: CELLULAR
  description: >
    The defining immunological abnormality. T cells are present in normal
    numbers and the T cell receptor repertoire is comparable to healthy
    controls, but the cells fail to proliferate and fail to produce cytokines
    on stimulation. This is a functional, not a developmental, combined
    immunodeficiency, which is the point at which STIM1 deficiency separates
    from the classical T-negative severe combined immunodeficiencies.
  biological_processes:
  - preferred_term: T cell cytokine production
    modifier: DECREASED
    term:
      id: GO:0002369
      label: T cell cytokine production
  - preferred_term: T cell proliferation
    modifier: DECREASED
    term:
      id: GO:0042098
      label: T cell proliferation
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A more consistent feature of all ORAI1- and STIM1-deficient T cells is a severe defect in the production of cytokines by CD4+ and CD8+ T cells, including production of IL-2, IL-4, IL-10, IFN-gamma, TNF-alpha, and IL-17A."
    explanation: >
      The review's synthesis across the published patients, stating the
      cytokine production defect that defines this node.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The distribution of CD4+ and CD8+ T cells, CD16+CD56+ NK cells, and CD19+ or CD20+ B cells in ORAI1- and STIM1-deficient patients is normal."
    explanation: >
      Establishes the normal lymphocyte counts that make this a defect of
      function rather than of development.
  downstream:
  - target: Uncontrolled Herpesvirus Infection
    description: >-
      Antiviral T cell populations are generated but are functionally
      insufficient to control chronic herpesvirus infection.
    causal_link_type: DIRECT
  - target: Combined immunodeficiency
    description: >-
      The clinical immunodeficiency is the consequence of the lymphocyte
      functional defect.
    causal_link_type: DIRECT
  - target: Recurrent infections
    description: >-
      Failure of T cell effector responses to bacterial, viral and fungal
      pathogens.
    causal_link_type: DIRECT
  - target: Impaired Antigen-Specific Antibody Response
    description: >-
      The humoral defect is attributed to failed CD4 T cell help rather than
      to a B cell-intrinsic requirement for calcium entry.
    causal_link_type: DIRECT

- name: Impaired Antigen-Specific Antibody Response
  biological_scale: ORGANISM
  description: >
    Humoral immunity is impaired in these patients, and the review attributes
    it to the impaired CD4 T cell function above rather than to a B
    cell-intrinsic lesion. The mouse work supports that reading: deleting both
    STIM paralogs in B cells alone leaves antigen-specific antibody responses,
    affinity maturation and germinal centre B cell numbers normal. This is the
    arm that immunoglobulin replacement substitutes for, and it is why the
    disease is combined rather than purely cellular.
  biological_processes:
  - preferred_term: immunoglobulin production
    modifier: DECREASED
    term:
      id: GO:0002377
      label: immunoglobulin production
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Taken together, it is likely that impaired CD4+ T cell function in ORAI1- and STIM1-deficient patients contributes to their compromised humoral immunity."
    explanation: >
      States both the humoral defect and the attribution to T cell help,
      which is why this node hangs off the T cell effector node.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "By contrast, these Stim1fl/flStim2fl/flMb1-Cre mice showed normal primary and memory antigen-specific antibody responses, normal affinity maturation and had similar numbers of germinal center B cells compared to wild type mice suggesting that SOCE is not required for humoral immunity."
    explanation: >
      The B cell-restricted double knockout has intact antibody responses,
      which is the negative result that makes the defect T cell-dependent
      rather than B cell-intrinsic. Graded INDIRECT because it supports the
      node's attribution by excluding the alternative.

- name: Impaired NK Cell Cytotoxic Function
  biological_scale: CELLULAR
  description: >
    Patient NK cells show defective granule exocytosis and reduced
    interferon-gamma production against tumour targets. This arm is
    independent of the T cell arm and was demonstrated in a kindred without
    overt clinical immunodeficiency, so it is a cellular defect that does not
    by itself determine the clinical picture. It contributes to the failure to
    control herpesvirus infection and plausibly to the herpesvirus-driven
    malignancy.
  biological_processes:
  - preferred_term: natural killer cell mediated cytotoxicity
    modifier: DECREASED
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:26560041
    reference_title: "A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The defect in NK cell SOCE was associated with impaired NK cell effector function, as shown by assays of granule exocytosis and intracellular IFN-gamma production in response to K562 tumor cells"
    explanation: >
      Reports the NK effector defect and the two assays behind it.
  downstream:
  - target: Uncontrolled Herpesvirus Infection
    description: >-
      Impaired NK cytotoxicity is a proposed contributor to the failure to
      contain chronic CMV and EBV infection.
    causal_link_type: DIRECT

- name: Reduced Regulatory T and Invariant NKT Cell Numbers
  biological_scale: CELLULAR
  description: >
    Regulatory T cells and invariant NKT cells are the only lymphocyte
    populations consistently reduced in CRAC channelopathy; every other subset
    is present in normal numbers. In one patient FOXP3-positive regulatory T
    cells were present but phenotypically abnormal while retaining normal
    suppressive function in vitro, so the deficit is better described as
    reduced and abnormal than as absent. This is the node the autoimmunity and
    the impaired antigen-specific antibody response are attributed to.
  biological_processes:
  - preferred_term: regulatory T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
  - preferred_term: NK T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0001865
      label: NK T cell differentiation
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
  - preferred_term: invariant natural killer T cell
    term:
      id: CL:0000921
      label: type I NK T cell
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Reduced numbers of lymphocyte populations in patients are limited to Foxp3+ Treg cells and iNKT cells, which likely account for some of the observed immune dysregulation, such as autoimmunity and impaired production of antigen-specific antibodies"
    explanation: >
      States both the restriction of the numerical deficit to these two
      populations and the attribution of the immune dysregulation to it.
  - reference: PMID:22190180
    reference_title: "Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "FOXP3-positive regulatory T (Treg) cells were present but showed an abnormal phenotype."
    explanation: >
      Qualifies the deficit: in this patient regulatory T cells were present
      and phenotypically abnormal rather than absent. Graded INDIRECT because
      it bears on the node by restricting what the numerical claim can mean
      rather than by asserting the reduction.
  downstream:
  - target: Loss of Peripheral Immune Tolerance
    description: >-
      Reduced regulatory T cell numbers remove the dominant mechanism
      maintaining tolerance to self antigens.
    causal_link_type: DIRECT

- name: Impaired Activation-Induced T Cell Death
  biological_scale: CELLULAR
  description: >
    Apoptosis of activated T cells terminates an immune response, and it is
    calcium-dependent. It was reported impaired in one STIM1-deficient patient
    and normal in two others, so the evidence is mixed. Where it is impaired
    it is the proposed explanation for the lymphoproliferation, which is
    otherwise paradoxical in a disease of failed lymphocyte activation.
  biological_processes:
  - preferred_term: activation-induced cell death of T cells
    modifier: DECREASED
    term:
      id: GO:0006924
      label: activation-induced cell death of T cells
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Impaired T cell apoptosis likely contributes to the lymphoproliferative phenotype of ORAI1- and STIM1-deficient patients."
    explanation: >
      The review's own hedged attribution of the lymphoproliferation to
      impaired T cell apoptosis. Graded INDIRECT because the review states it
      as a likely contribution rather than a demonstrated mechanism, and the
      underlying patient data disagree between reports.
  downstream:
  - target: Lymphoproliferation
    description: >-
      Failure to delete activated T cells permits their accumulation.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - The step from impaired apoptosis to clinical lymphoproliferation is proposed rather than demonstrated in patients

- name: Loss of Peripheral Immune Tolerance
  biological_scale: ORGANISM
  description: >
    Autoimmunity in STIM1 deficiency is mild and largely confined to
    autoimmune cytopenias, unlike the multi-organ autoimmunity of regulatory
    T cell deficiency in IPEX. The review attributes that restriction to
    residual regulatory T cells with normal suppressive function, and to the
    fact that effector T cell function is also impaired, so the autoreactive
    cells that escape tolerance are themselves poorly functional.

    Autoimmunity is commoner here than in the sibling disease ORAI1
    deficiency, and whether that difference is real is unsettled. The review
    that reports it also cautions that the ORAI1 patients are few and died
    early, so they may simply not have lived long enough to develop what
    STIM1-deficient patients develop. Both readings are recorded rather than
    one being chosen.
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A more likely explanation for the patients' autoimmunity is the reduced frequency of CD25+ FOXP3+ Treg cells found in the blood of several STIM1-deficient patients"
    explanation: >
      The review's attribution of the autoimmunity to the reduced frequency of
      regulatory T cells, which is the claim this node makes.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
    snippet: "Given the small numbers of patients with LoF mutations and their early mortality, it is difficult to say for certain if autoimmunity really is less likely in ORAI1-deficient patients, or if they would develop disease if they did not succumb to immunodeficiency or were treated by HSCT."
    explanation: >
      The review's own caution about the ORAI1-versus-STIM1 autoimmunity
      difference this node records. Graded INDIRECT because it bears on the
      node by limiting what the comparison can be read to mean rather than by
      asserting the loss of tolerance itself.
  downstream:
  - target: Autoimmune hemolytic anemia
    description: >-
      Coombs-positive autoimmune haemolytic anaemia, usually in the first year
      of life.
    causal_link_type: DIRECT
  - target: Autoimmune thrombocytopenia
    description: >-
      Immune thrombocytopenia, in most patients accompanying the haemolytic
      anaemia.
    causal_link_type: DIRECT

- name: Lymphoproliferation
  biological_scale: ORGANISM
  description: >
    Hepatosplenomegaly and lymphadenopathy from accumulation of lymphocytes,
    with severe T cell tissue infiltrates in the most severe reported case.
    This is one of the two features that distinguish STIM1 deficiency from
    ORAI1 deficiency, and it is the target of the rapamycin treatment reported
    in 2024.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lymphoproliferation is a common feature of patients with LoF mutations in STIM1"
    explanation: >
      States that lymphoproliferation is common in loss-of-function STIM1
      disease, which is what this node asserts.
  - reference: PMID:38578569
    reference_title: "Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphoproliferation was associated with severe T-cell infiltrates."
    explanation: >
      Documents the tissue correlate of the lymphoproliferation in a patient
      with complete loss of STIM1 protein.
  downstream:
  - target: Lymphadenopathy
    description: >-
      Lymph node enlargement from lymphocyte accumulation.
    causal_link_type: DIRECT
  - target: Hepatosplenomegaly
    description: >-
      Liver and spleen enlargement from lymphocyte accumulation and
      infiltration.
    causal_link_type: DIRECT

- name: Uncontrolled Herpesvirus Infection
  biological_scale: ORGANISM
  description: >
    Chronic CMV and EBV infection despite the presence of antiviral T cell
    populations that proliferate to viral antigen and show normal cytotoxicity
    in vitro, and fatal disseminated HHV-8-driven Kaposi sarcoma in a child
    whose only other abnormality was the STIM1 genotype. Herpesvirus control
    is the arm of immunity that fails most conspicuously, and the Kaposi
    sarcoma case is the evidence that it fails in a T-cell-dependent way.
  evidence:
  - reference: PMID:22190180
    reference_title: "Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells."
    explanation: >
      States the failure of herpesvirus control and the two cellular
      contributions the authors propose for it.
  downstream:
  - target: Kaposi's sarcoma
    description: >-
      HHV-8 infection progressing to disseminated Kaposi sarcoma in the
      absence of effective T cell control.
    causal_link_type: DIRECT
  - target: Recurrent viral infections
    description: >-
      Chronic and recurrent viral infection is the clinical expression of the
      failed antiviral response.
    causal_link_type: DIRECT

- name: Impaired Skeletal Muscle Calcium Handling
  biological_scale: TISSUE
  description: >
    Store-operated calcium entry refills sarcoplasmic reticulum calcium stores
    during sustained activity, and skeletal muscle needs it: myotubes without
    functional STIM1 fatigue rapidly, and mice without functional STIM1 die
    perinatally of a skeletal myopathy. In patients the consequence is a
    congenital, non-progressive global muscular hypotonia without structural
    abnormality on biopsy, which is the form the muscle involvement takes in
    the loss-of-function CRAC channelopathies.
  biological_processes:
  - preferred_term: skeletal muscle contraction
    modifier: DECREASED
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:18488020
    reference_title: "STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly. Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy."
    explanation: >
      Establishes that skeletal muscle requires STIM1-dependent SOCE for
      contractile function, which is the mechanism behind the patients'
      hypotonia.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "LoF or null mutations in ORAI1 and STIM1 resulted in congenital, non-progressive muscular hypotonia in all but one patient"
    explanation: >
      States the human correlate, including that it is congenital and
      non-progressive, which distinguishes it from the progressive myopathy of
      the gain-of-function diseases.
  downstream:
  - target: Generalized hypotonia
    description: >-
      Congenital non-progressive global muscular hypotonia.
    causal_link_type: DIRECT
  - target: Muscle weakness
    description: >-
      Weakness accompanying the hypotonia, reported across the severity range.
    causal_link_type: DIRECT

- name: Defective Enamel Mineralization
  biological_scale: TISSUE
  description: >
    Ameloblasts secrete the enamel matrix and supply the calcium that
    mineralizes it, and they depend on store-operated calcium entry to do so.
    In mice lacking STIM1 and STIM2 in enamel cells the enamel is
    hypomineralized, thinner and mechanically weak, the ameloblasts lose their
    ruffled border, and the cells show ER stress and mitochondrial
    dysfunction. In patients the result is a generalized developmental enamel
    defect, and because the requirement persists after birth the later
    erupting permanent teeth are affected too, including in patients who
    survive the immunodeficiency.
  biological_processes:
  - preferred_term: enamel mineralization
    modifier: DECREASED
    term:
      id: GO:0070166
      label: enamel mineralization
  cell_types:
  - preferred_term: ameloblast
    term:
      id: CL:0000059
      label: ameloblast
  evidence:
  - reference: PMID:28352661
    reference_title: "Store-operated Ca(2+) entry controls ameloblast cell function and enamel development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Enamel in Stim1/2K14cre mice was hypomineralized with decreased Ca content, mechanically weak, and thinner."
    explanation: >
      Establishes the mechanism of the enamel defect in an animal model built
      specifically because the human enamel phenotype had no explanation.
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also had a defect in enamel dentition, which became apparent in the first years of life."
    explanation: >
      The human enamel phenotype in the founding kindred, and its early
      onset.
  downstream:
  - target: Amelogenesis imperfecta
    description: >-
      Generalized developmental enamel abnormality.
    causal_link_type: DIRECT

- name: Sweat Gland Secretory Failure
  biological_scale: TISSUE
  description: >
    Eccrine sweat glands develop normally but cannot secrete. SOCE is required
    to activate the calcium-activated chloride channel ANO1, and without
    chloride secretion there is no fluid secretion. CRAC channel-deficient
    patients and mice with ectodermal deletion of Stim1 and Stim2 both fail to
    sweat, and the clinical consequence is hypohidrosis with heat intolerance.
  biological_processes:
  - preferred_term: sweat secretion
    modifier: DECREASED
    term:
      id: GO:0160269
      label: sweat secretion
  evidence:
  - reference: PMID:27721237
    reference_title: "Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we have shown that CRAC channel-deficient patients and mice with ectodermal tissue-specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development."
    explanation: >
      Establishes that the failure is secretory rather than developmental, in
      patients as well as in mice.
  downstream:
  - target: Hypohidrosis
    description: >-
      Reduced sweating, with heat intolerance at high ambient temperature.
    causal_link_type: DIRECT
phenotypes:
- category: Immunological
  name: Combined immunodeficiency
  description: >
    A SCID-like clinical immunodeficiency with recurrent and chronic viral,
    bacterial and fungal infection beginning in the first years of life,
    arising from impaired lymphocyte function rather than impaired lymphocyte
    development.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A principal feature of most cases of combined immunodeficiency disease is impaired function of T, B, or natural killer cells, despite their normal development."
    explanation: >
      The founding report's framing of the disease it is describing, which is
      the function-not-development distinction this phenotype records.
- category: Immunological
  name: Recurrent infections
  description: >
    Recurrent and severe infection with viral, bacterial and fungal pathogens,
    typically presenting in the first year of life in the severe cases.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "ORAI1- and STIM1-deficient patients suffer from recurrent and severe infections with viral, bacterial and fungal pathogens"
    explanation: >
      The review's statement of the infection phenotype across the published
      patients.
  sequelae:
  - target: Pneumonia
    description: >-
      Respiratory infection is a common presentation and a common cause of
      death in these patients.
    causal_link_type: DIRECT
- category: Immunological
  name: Recurrent viral infections
  description: >
    Chronic and recurrent viral infection, with chronic cytomegalovirus and
    Epstein-Barr virus infection documented despite the presence of antiviral
    T cells.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:22190180
    reference_title: "Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections"
    explanation: >
      Documents chronic herpesvirus infection in a patient with a homozygous
      STIM1 missense allele.
- category: Immunological
  name: Autoimmune hemolytic anemia
  description: >
    Coombs-positive autoimmune haemolytic anaemia, usually appearing in the
    first year of life and requiring glucocorticoids. With thrombocytopenia it
    is the characteristic autoimmune manifestation of the disease.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Most of these patients also develop Coombs-positive autoimmune hemolytic anemia (AIHA) and thrombocytopenia in their first year of life."
    explanation: >
      States both the character of the anaemia and its timing across the
      published loss-of-function STIM1 patients.
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 15 months she was found to have autoimmune hemolytic anemia, and at 5 years thrombocytopenia, both of which were treated with glucocorticoids"
    explanation: >
      The individual clinical course in the founding kindred, including the
      treatment given.
- category: Immunological
  name: Autoimmune thrombocytopenia
  description: >
    Immune thrombocytopenia, in most patients accompanying the autoimmune
    haemolytic anaemia.
  phenotype_term:
    preferred_term: Autoimmune thrombocytopenia
    term:
      id: HP:0001973
      label: Autoimmune thrombocytopenia
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She had a clinical picture similar to that of her older sister, including severe autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatosplenomegaly, partial iris hypoplasia, and muscular hypotonia."
    explanation: >
      Documents thrombocytopenia as part of the syndrome in a second affected
      sibling, alongside the other features of the entry.
- category: Immunological
  name: Lymphadenopathy
  description: >
    Lymph node enlargement from lymphoproliferation, present from infancy in
    the severe cases.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphadenopathy and hepatosplenomegaly were apparent at 7 months of age"
    explanation: >
      Documents lymphadenopathy and its age of onset in the index patient.
- category: Hematological
  name: Hepatosplenomegaly
  description: >
    Liver and spleen enlargement from lymphocyte accumulation and tissue
    infiltration.
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on three siblings from one kindred with a clinical syndrome of immunodeficiency, hepatosplenomegaly, autoimmune hemolytic anemia, thrombocytopenia, muscular hypotonia, and defective enamel dentition."
    explanation: >
      Lists hepatosplenomegaly among the defining features of the syndrome in
      the founding kindred.
- category: Neoplastic
  name: Kaposi's sarcoma
  description: >
    Disseminated HHV-8-driven Kaposi sarcoma, fatal at two years of age in a
    child whose STIM1 genotype was the only identified abnormality. Classic
    Kaposi sarcoma in childhood is otherwise exceedingly rare, which is why
    this single case carries mechanistic weight.
  phenotype_term:
    preferred_term: Kaposi sarcoma
    term:
      id: HP:0100726
      label: Kaposi's sarcoma
  evidence:
  - reference: PMID:20876309
    reference_title: "Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a child with no other unusually severe infectious or tumoral phenotype who died from disseminated KS at two years of age."
    explanation: >
      Documents the Kaposi sarcoma and, importantly, that it was the
      presenting and isolated severe phenotype in this child.
- category: Musculoskeletal
  name: Generalized hypotonia
  description: >
    Congenital, non-progressive global muscular hypotonia. Muscle biopsy and
    electromyography were normal in the index patient, and the hypotonia
    persists after haematopoietic stem cell transplantation.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
    clinical_course: STABLE
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite normal early cognitive development, the neonatal period of Patient V-1 was conspicuous because of partial iris hypoplasia and nonprogressive global muscular hypotonia"
    explanation: >
      Documents the hypotonia, its congenital onset and its non-progressive
      course, which is what `clinical_course: STABLE` records.
- category: Musculoskeletal
  name: Muscle weakness
  description: >
    Muscle weakness, reported in patients at both ends of the severity range:
    in a child whose presentation was combined immunodeficiency with
    congenital myopathy, and in siblings whose presentation was
    connective-tissue rather than immunological.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:40411647
    reference_title: "A novel variant in the STIM1 gene leading to combined immunodeficiency and congenital myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with recurrent pneumonia, blood-streaked diarrhea, eczema, muscle weakness, and failure to thrive."
    explanation: >
      Lists muscle weakness among the presenting features in a patient with a
      novel homozygous STIM1 missense allele.
  - reference: PMID:33733462
    reference_title: "A novel bi-allelic loss-of-function mutation in STIM1 expands the phenotype of STIM1-related diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with muscle weakness, hyperlaxity, elastic skin, tooth abnormalities, dysmorphic facies, hypoplastic patellae and history of respiratory infections"
    explanation: >
      The same feature in the protein-null siblings whose presentation was
      otherwise unlike the classical immunodeficiency picture, which is the
      breadth this entry's notes record.
- category: Dental
  name: Amelogenesis imperfecta
  description: >
    A generalized developmental enamel defect apparent in the first years of
    life and affecting the permanent as well as the deciduous dentition,
    because the requirement for store-operated calcium entry in ameloblasts
    persists after birth.
  phenotype_term:
    preferred_term: Amelogenesis imperfecta
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  evidence:
  - reference: PMID:26560041
    reference_title: "A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a consanguineous family, segregating a novel syndrome of recessive AI and hypohidrosis by using autozygosity mapping and clonal sequencing."
    explanation: >
      Reports amelogenesis imperfecta, abbreviated AI in this paper, together
      with hypohidrosis as the presenting syndrome in a STIM1-mutant kindred.
- category: Integumentary
  name: Hypohidrosis
  description: >
    Reduced sweating with heat intolerance, from secretory failure of
    structurally normal eccrine sweat glands.
  phenotype_term:
    preferred_term: Hypohidrosis
    term:
      id: HP:0000966
      label: Hypohidrosis
  evidence:
  - reference: PMID:27721237
    reference_title: "Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures"
    explanation: >
      States the sweating phenotype and the heat intolerance that follows from
      it in CRAC channel-deficient patients.
- category: Ophthalmologic
  name: Hypoplasia of the iris
  description: >
    Partial iris hypoplasia, present from the neonatal period and persisting
    after haematopoietic stem cell transplantation.
  phenotype_term:
    preferred_term: Partial iris hypoplasia
    term:
      id: HP:0007676
      label: Hypoplasia of the iris
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, at 6 years of age, he has nonprogressive muscular hypotonia and partial iris hypoplasia only."
    explanation: >
      Documents the iris hypoplasia, and that it is one of the two features
      remaining after successful transplantation.
- category: Ophthalmologic
  name: Mydriasis
  description: >
    Mydriasis, in one patient with light-insensitive pupils. Reported in
    several patients alongside the iris hypoplasia.
  phenotype_term:
    preferred_term: Mydriasis
    term:
      id: HP:0011499
      label: Mydriasis
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "partial iris hypoplasia and/or mydriasis"
    explanation: >
      The review's statement of the ocular finding across ORAI1- and
      STIM1-deficient patients.
- category: Respiratory
  name: Pneumonia
  description: >
    Recurrent pneumonia, a common presentation and a common cause of death in
    the severe cases.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:40411647
    reference_title: "A novel variant in the STIM1 gene leading to combined immunodeficiency and congenital myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with recurrent pneumonia, blood-streaked diarrhea, eczema, muscle weakness, and failure to thrive."
    explanation: >
      Documents recurrent pneumonia as a presenting feature in a patient with
      a novel homozygous STIM1 missense allele.
genetic:
- name: STIM1
  gene_term:
    preferred_term: STIM1
    term:
      id: hgnc:11386
      label: STIM1
  relationship_type: CAUSATIVE
  notes: >
    STIM1 encodes stromal interaction molecule 1, the endoplasmic reticulum
    calcium sensor of the CRAC channel complex. Biallelic loss-of-function
    variants cause this disease. Autosomal dominant gain-of-function variants
    in the same gene cause a separate spectrum, namely tubular aggregate
    myopathy, York platelet syndrome and Stormorken syndrome, which is not
    curated here.
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of these patients have a homozygous nonsense mutation in STIM1 that abrogates expression of STIM1 and Ca(2+) influx."
    explanation: >
      The gene-disease assertion, from the report that established it.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes."
    explanation: >
      Supports the scope statement in this record: the same gene carries a
      distinct gain-of-function disease spectrum that this entry excludes.
animal_models:
- name: Stim1 null mouse
  species: Mouse
  genotype: Stim1 loss-of-function (null)
  publication: PMID:18488020
  description: >
    Mice lacking functional STIM1 die perinatally of a skeletal myopathy, and
    their myotubes show no store-operated calcium entry and fatigue rapidly.
    The model establishes the muscle arm of the human disease. Its perinatal
    lethality is itself a species difference: human patients with complete
    loss of STIM1 protein survive with a non-progressive hypotonia.
  modeled_mechanisms:
  - target: Impaired Skeletal Muscle Calcium Handling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >
      Reproduces the loss of store-operated calcium entry in muscle and its
      contractile consequence.
    limitations: >-
      The mouse dies perinatally of myopathy whereas the human phenotype is a
      survivable non-progressive hypotonia, so the model overstates the
      severity of the muscle arm. The measurement is made in myotubes, which
      is a cellular readout for a tissue-level node.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Perinatal lethality from skeletal myopathy has no counterpart in
        patients with protein-null STIM1 genotypes, who survive with
        non-progressive hypotonia. The direction of the difference matters:
        the model is more severe than the disease.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        Store-operated calcium entry and fatigue are measured in cultured
        myotubes, while the node is the tissue-level calcium-handling defect
        of skeletal muscle in vivo.
    readouts:
    - name: Store-operated calcium entry in myotubes
      target: Impaired Skeletal Muscle Calcium Handling
      direction: ABOLISHED
      interpretation: The cellular lesion in muscle, in the same direction as in patient cells.
      evidence:
      - reference: PMID:18488020
        reference_title: "STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Myotubes lacking functional STIM1 fail to show SOC and fatigue rapidly."
        explanation: Reports the abolished store-operated calcium entry and the contractile consequence.
    evidence:
    - reference: PMID:18488020
      reference_title: "STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, mice lacking functional STIM1 die perinatally from a skeletal myopathy."
      explanation: >
        Establishes that STIM1 loss produces a skeletal myopathy in vivo,
        which is what makes this model informative for the muscle node.
- name: T cell-specific Stim1 Stim2 double knockout mouse
  species: Mouse
  genotype: Stim1 and Stim2 conditional deletion in T cells (Cd4-Cre)
  publication: PMID:18327260
  description: >
    T cell-specific deletion of both STIM calcium sensors reproduces the two
    features that distinguish human STIM1 deficiency from ORAI1 deficiency,
    namely lymphoproliferation and a selective reduction in regulatory T cell
    numbers. Note the model deletes both STIM1 and STIM2: the review records
    that regulatory and NKT cells are absent only in the double-deficient
    mouse and not in the STIM1 single knockout, which is why the human
    reduction is partial rather than absolute.
  modeled_mechanisms:
  - target: Reduced Regulatory T and Invariant NKT Cell Numbers
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >
      Reproduces the selective loss of regulatory T cells, but only when both
      STIM paralogs are deleted.
    limitations: >-
      Human disease is STIM1-only, and the mouse requires additional Stim2
      deletion to abolish these populations, so the genotype is more severe
      than the human genotype. The deletion is also T cell-restricted, so
      non-immune arms of the disease are outside the model.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The model deletes Stim1 and Stim2 together, where patients lose STIM1
        alone and retain STIM2. Residual STIM2-dependent calcium entry is the
        stated reason the human deficit in these populations is partial.
    - divergence_type: BOUNDARY_OMISSION
      materiality: IMMATERIAL
      description: >-
        Deletion is restricted to T cells, so the muscle, enamel and sweat
        gland arms of the disease are not in the model. That does not bear on
        this link, which concerns a T cell population.
    readouts:
    - name: Regulatory T cell numbers
      target: Reduced Regulatory T and Invariant NKT Cell Numbers
      direction: DECREASED
      interpretation: The same direction as the reduced regulatory T cell frequency in patients.
      evidence:
      - reference: PMID:18327260
        reference_title: "Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "T cell-specific ablation of both STIM1 and STIM2 resulted in a notable lymphoproliferative phenotype and a selective decrease in regulatory T cell numbers."
        explanation: Reports the selective reduction in regulatory T cells in the double knockout.
    evidence:
    - reference: PMID:18327260
      reference_title: "Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that both STIM1 and STIM2 promote store-operated Ca2+ entry into T cells and fibroblasts and that STIM proteins are required for the development and function of regulatory T cells."
      explanation: >
        States the requirement for STIM proteins in regulatory T cell
        development, which is the claim this link rests on.
- name: Ectodermal Stim1 Stim2 double knockout mouse
  species: Mouse
  genotype: Stim1 and Stim2 conditional deletion in ectodermal tissue (K14-Cre)
  publication: PMID:27721237
  description: >
    Deletion of both STIM sensors in ectodermal tissue abolishes sweating
    despite normal sweat gland development, and produces hypomineralized,
    thin, mechanically weak enamel with abnormal ameloblast morphology. The
    model was built because the human enamel and sweating phenotypes had no
    mechanistic explanation, and it supplies both.
  modeled_mechanisms:
  - target: Sweat Gland Secretory Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >
      Reproduces the secretory failure of structurally normal sweat glands,
      and identifies the calcium-activated chloride channel step.
    limitations: >-
      As with the other conditional models, both STIM paralogs are deleted
      where patients lose only STIM1.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Stim1 and Stim2 are deleted together, a more complete loss of
        store-operated calcium entry than the human STIM1-only genotype.
    readouts:
    - name: Sweat production
      target: Sweat Gland Secretory Failure
      direction: ABOLISHED
      interpretation: Matches the hypohidrosis of patients, with glands present.
      evidence:
      - reference: PMID:27721237
        reference_title: "Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "SOCE was absent in agonist-stimulated sweat glands from Orai1K14Cre and Stim1/2K14Cre mice and human sweat gland cells lacking ORAI1 or STIM1 expression."
        explanation: Reports the abolished response in the model and, in parallel, in human cells.
  - target: Defective Enamel Mineralization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: TISSUE
    description: >
      Reproduces the enamel defect and identifies the ameloblast changes and
      the oxidative and ER stress behind it.
    limitations: >-
      Both STIM paralogs are deleted, and the mechanistic chain from
      ameloblast ER stress to hypomineralization is established in the mouse
      rather than in patient tissue.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Stim1 and Stim2 are deleted together, where patients retain STIM2.
    readouts:
    - name: Enamel mineral content
      target: Defective Enamel Mineralization
      direction: DECREASED
      interpretation: The structural correlate of the patients' amelogenesis imperfecta.
      evidence:
      - reference: PMID:28352661
        reference_title: "Store-operated Ca(2+) entry controls ameloblast cell function and enamel development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Enamel in Stim1/2K14cre mice was hypomineralized with decreased Ca content, mechanically weak, and thinner."
        explanation: Reports the reduced mineral content and the mechanical consequence.
    evidence:
    - reference: PMID:28352661
      reference_title: "Store-operated Ca(2+) entry controls ameloblast cell function and enamel development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The cause of these enamel defects has remained unclear given a lack of animal models."
      explanation: >
        States why this model exists: the human enamel defect had no
        mechanistic account before it, which is what makes it informative for
        this node.
diagnosis:
- name: Store-operated calcium entry measurement
  description: >
    Functional demonstration of impaired or absent store-operated calcium
    entry in patient T cells or fibroblasts, by calcium imaging after store
    depletion. This is the assay that defines the CRAC channelopathies as a
    group, and it does not distinguish STIM1 from ORAI1 deficiency: the gene
    test does that.
  evidence:
  - reference: PMID:38977117
    reference_title: "Store-operated calcium entry dysfunction in CRAC channelopathy: Insights from a novel STIM1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function."
    explanation: >
      Describes the functional assay and what a positive result establishes,
      in a patient diagnosed by this route.
- name: STIM1 sequencing
  description: >
    Molecular confirmation by exome sequencing, a primary immunodeficiency
    gene panel, or targeted STIM1 sequencing. In a patient with combined
    immunodeficiency plus hypohidrosis and enamel defects, STIM1 and ORAI1 are
    the two genes to sequence together, since they produce a nearly
    superimposable syndrome and only the genotype separates them.
  evidence:
  - reference: PMID:33733462
    reference_title: "A novel bi-allelic loss-of-function mutation in STIM1 expands the phenotype of STIM1-related diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1"
    explanation: >
      Exome sequencing as the route to molecular diagnosis in a kindred whose
      presentation was not the classical immunodeficiency picture.
discussions:
- discussion_id: stim1_protein_loss_does_not_predict_severity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why does complete loss of STIM1 protein not predict the severity of the
    immunodeficiency?
  attaches_to:
  - pathophysiology#Biallelic Loss-of-Function STIM1 Variants
  rationale: >
    Two siblings homozygous for a frameshift allele that abolishes STIM1
    protein presented with a connective-tissue and skeletal picture rather
    than with severe immune disease, while missense alleles that leave protein
    expressed have produced fatal infection in infancy. So neither the allele
    class nor the presence of protein orders the clinical severity. The
    obvious candidate is the paralog STIM2, which has a lower activation
    threshold and is intact in these patients, but no study has tested whether
    STIM2 levels track the clinical severity in human patients.
- discussion_id: stim1_vs_orai1_autoimmunity_difference
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is autoimmunity genuinely commoner in STIM1 deficiency than in ORAI1
    deficiency, or is the difference an artefact of cohort size and early
    death?
  attaches_to:
  - pathophysiology#Loss of Peripheral Immune Tolerance
  rationale: >
    The two diseases are otherwise near-identical, and lymphoproliferation and
    autoimmune cytopenias are the one axis on which they are reported to
    differ. The review that reports the difference also says it cannot be
    settled, because the ORAI1 patients are few and several died before the
    age at which STIM1-deficient patients develop cytopenias. Settling it
    needs either more ORAI1 patients or longer follow-up of transplanted ones,
    not a new experiment.
- discussion_id: aicd_impairment_and_lymphoproliferation
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does impaired activation-induced T cell death actually drive the
    lymphoproliferation?
  attaches_to:
  - pathophysiology#Impaired Activation-Induced T Cell Death
  rationale: >
    This is the standard explanation for the paradox that a disease of failed
    T cell activation produces T cell accumulation, and the patient data are
    mixed: apoptosis after CD3 stimulation was impaired in one STIM1-deficient
    patient and normal in two others. The review itself puts it no higher than
    "likely contributes". Until it is measured in more patients, the edge from
    this node to the lymphoproliferation stays typed as having unidentified
    intermediates.
- discussion_id: stim1_null_mouse_muscle_severity_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Why does the STIM1-null mouse die perinatally of skeletal myopathy when
    protein-null human patients survive with a non-progressive hypotonia?
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Impaired Skeletal Muscle Calcium Handling
  rationale: >
    The direction of the mismatch is what makes it interesting: the model is
    more severe than the disease, not less. Mice lacking functional STIM1 die
    perinatally of a skeletal myopathy, while patients with frameshift alleles
    that abolish STIM1 protein reach adulthood with a static hypotonia and no
    structural abnormality on biopsy. Something compensates in human muscle
    and not in mouse muscle, and until that is identified the mouse cannot be
    used to predict how far the human muscle phenotype could be corrected.
treatments:
- name: Hematopoietic Stem Cell Transplantation
  description: >
    Allogeneic haematopoietic stem cell transplantation is what the severe
    immunodeficiency requires, and it is curative for the immunological arm.
    It does not correct the non-haematopoietic arms: the transplanted survivor
    in the founding kindred retained his hypotonia and iris hypoplasia, and
    the permanent dentition of survivors still requires extensive dental work.
    Outcomes in the published cohort are mixed, with deaths from transplant
    complications and from comorbid conditions.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: haematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired T Cell Effector Function
    description: >-
      Replaces the patient's haematopoietic system, and with it the
      STIM1-deficient lymphocytes.
  evidence:
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The clinical phenotype of patients with null or LoF mutations in ORAI1 or STIM1 is dominated by life-threatening immunodeficiency that typically manifests in the first year of life and requires hematopoietic stem cell therapy (HSCT) to control the disease."
    explanation: >
      States that transplantation is what controls the disease, which is the
      basis for recording it as the definitive treatment.
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, at 6 years of age, he has nonprogressive muscular hypotonia and partial iris hypoplasia only."
    explanation: >
      Documents the limit of what transplantation achieves: the immunological
      and autoimmune features resolved, the muscle and eye features did not.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Four patients survived after HSCT, 3 died from comorbid conditions or failed HSCT, and 3 survived without HSCT, presumably due to hypomorphic mutations"
    explanation: >
      The outcome tally across the published CRAC channelopathy cohort, which
      is why this record does not describe transplantation as uniformly
      successful.
- name: Sirolimus
  description: >
    The mTOR inhibitor rapamycin was used in a patient with complete loss of
    STIM1 protein and severe lymphoproliferation; it controlled the
    lymphoproliferation and improved T cell activation and proliferation
    capacity. This is a single reported patient, and the authors present it as
    a first use in this disorder rather than as established practice.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Lymphoproliferation
    description: >-
      Directed at the lymphoproliferative arm rather than at the underlying
      calcium signalling defect.
  evidence:
  - reference: PMID:38578569
    reference_title: "Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment with rapamycin controlled lymphoproliferation, improved T-cell activation and proliferation capacities"
    explanation: >
      Reports the clinical and immunological response in the single treated
      patient.
  - reference: PMID:38578569
    reference_title: "Rapamycin Controls Lymphoproliferation and Reverses T-Cell Responses in a Patient with a Novel STIM1 Loss-of-Function Deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reveals for the first time the potential therapeutic utility of rapamycin for this disorder"
    explanation: >
      The authors' own framing, which is why this record describes the
      evidence as a single reported use rather than established practice.
- name: Glucocorticoid Therapy for Autoimmune Cytopenias
  description: >
    The autoimmune haemolytic anaemia and thrombocytopenia were treated with
    glucocorticoids in the founding kindred. This is symptomatic treatment of
    the autoimmune arm, not disease-modifying therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Loss of Peripheral Immune Tolerance
    description: >-
      Suppresses the autoimmune effector response rather than restoring
      tolerance.
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "at 15 months she was found to have autoimmune hemolytic anemia, and at 5 years thrombocytopenia, both of which were treated with glucocorticoids"
    explanation: >
      Documents glucocorticoid treatment of both autoimmune cytopenias.
- name: Immunoglobulin Replacement
  description: >
    Intravenous immunoglobulin was given for the humoral defect and was
    stopped after successful transplantation in the founding kindred, which is
    itself evidence that the humoral arm is corrected by transplantation.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  target_mechanisms:
  - target: Impaired Antigen-Specific Antibody Response
    description: >-
      Substitutes for the antibody response that fails downstream of impaired
      T cell help, rather than acting on the calcium signalling defect.
  evidence:
  - reference: PMID:19420366
    reference_title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient V-7 survived after hematopoietic stem-cell transplantation (with a healthy, HLA-identical sister as donor) performed at 15 months of age, and intravenous immune globulin was stopped."
    explanation: >
      Documents immunoglobulin replacement and that it was discontinued once
      the transplant had reconstituted the immune system.
references:
- reference: PMID:19420366
  title: "STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity."
- reference: PMID:26469693
  title: "Diseases caused by mutations in ORAI1 and STIM1."

📚

References & Deep Research

References

PMID:19420366

STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity.

No top-level findings curated for this source.

PMID:26469693

Diseases caused by mutations in ORAI1 and STIM1.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

Ultra-rare. The published cohort is a small number of kindreds: the founding family with a homozygous nonsense allele in STIM1 exon 3 (Picard et al., NEJM 2009), two siblings homozygous for p.R429C (Fuchs et al., 2012), a child with a homozygous splice-site allele who died of Kaposi sarcoma (Byun et al., 2010), two cousins homozygous for the EF-hand allele p.L74P (Parry et al., 2016), two siblings homozygous for c.685delT (Salvi et al., 2021), and further single patients since. Counts in this entry are therefore counts of kindreds or patients, never frequencies, and `frequency` is deliberately left unset throughout. The disease is one of lymphocyte function, not lymphocyte development. T, B and NK cell numbers are normal, and the defect appears on stimulation. That is what separates it from the classical T-B-NK- severe combined immunodeficiencies its SCID-like presentation invites comparison with, and it is why the pathograph routes through cytokine transcription rather than through a lymphopoiesis node. The phenotype is wider at the mild end than the SCID-like description suggests, and this matters for reading a new patient. Two cousins homozygous for p.L74P had amelogenesis imperfecta and hypohidrosis with grossly abnormal lymphocyte and NK cell SOCE but no overt clinical immunodeficiency, and two siblings with a frameshift allele abolishing STIM1 protein entirely presented with a connective-tissue and skeletal picture rather than with immune disease. So neither the allele class nor the absence of protein predicts immunological severity, and the nodes below record the mechanism rather than a uniform clinical outcome. The sibling disease is ORAI1 deficiency (MONDO:0013007), curated as `kb/disorders/ORAI1_Deficiency.yaml`. Both sit under `combined immunodeficiency due to CRAC channel dysfunction` (MONDO:0015695), and the 2015 review calls the two phenotypes almost identical, naming lymphoproliferation and autoimmune cytopenias as the apparent difference while cautioning that the small patient numbers and early mortality in ORAI1 deficiency may be what produces it. That caution is recorded on the `Loss of Peripheral Immune Tolerance` node rather than resolved here. No `has_subtypes` relationship is asserted between the two: they are separate genes and separate MONDO concepts, and the right structure for the pair is a future grouping. STIM1 is a two-faced gene, and this entry is only one of its faces. Autosomal dominant gain-of-function STIM1 variants constitutively activate the CRAC channel and cause tubular aggregate myopathy, York platelet syndrome and Stormorken syndrome. Those are not STIM1 deficiency and are not curated here. The distinction is practical: a literature search on STIM1 returns both, and the myopathy in the gain-of-function diseases is a different lesion from the congenital hypotonia described below, despite both being muscle. Miosis in Stormorken syndrome and iris hypoplasia or mydriasis here are likewise different eye findings. `channelopathy_category` is deliberately unset, for the same reason the ORAI1 entry gives: `ChannelopathyOrganSystemEnum` offers cardiac, skeletal muscle, neurological and epithelial, and none of them names an immune channelopathy, which is what this disease principally is. The enum needs an immune value rather than this entry needing a wrong one. No `conforms_to` was declared. The module directory was searched and none matches: this is a channel-gated transcription-factor activation failure, not an inflammatory, fibrotic or degeneration chain. If a calcium-signalling-failure module is ever created, this entry and ORAI1 deficiency are its first two conformers. A splice-correcting antisense oligonucleotide has been reported to improve STIM1 splicing in cells from a patient with a splice-site allele. It is recorded here rather than in `treatments:` because it was tested in patient cells only, has been given to nobody, and would apply only to splice-altering genotypes. Note also that the CRAC-channel modulators in development are blockers, aimed at gain-of-function and inflammatory indications; a blocker is the wrong direction for a loss-of-function disease. Deep-research provenance. An OpenScientist run (`research/STIM1_Deficiency-deep-research-openscientist.md`) is committed alongside this entry. `just preflight-dr` scores it WARN, on the ORAI1 mention count rather than on anything wrong: STIM1 is mentioned 98 times and ORAI1 32, and ORAI1 is this disease's own partner protein, which is the ambiguity the check's own message says a mention count cannot resolve. The report contributed the diagnostic workup and the antisense oligonucleotide note above. Every quote used here was re-verified against the fetched reference cache rather than taken from the report.

Create: STIM1_Deficiency · 2026-09-29T21:54:45Z · View source

Created the STIM1 deficiency entry (MONDO:0013008), the CRAC channelopathy sibling of the existing ORAI1_Deficiency entry, from primary literature checked against the fetched reference cache. The pathograph runs from biallelic STIM1 loss through failed ER store sensing and abolished store-operated calcium entry to five arms: the calcineurin-NFAT transcriptional failure and its T cell, regulatory T cell and humoral consequences, NK cytotoxic failure, skeletal muscle calcium handling, ameloblast enamel mineralization, and sweat gland secretion. All 15 phenotypes are causally connected. An OpenScientist deep-research run is committed alongside. preflight-dr returns WARN, on the ORAI1 mention count (STIM1 98, ORAI1 32) rather than on anything wrong, since ORAI1 is this disease's own partner protein. The report supplied the diagnostic workup and the antisense oligonucleotide note; every quote used was re-verified against the cache rather than taken from the report. The report offered HP:0000535 for the ocular phenotype, which is obsolete and is in any case Sparse and thin eyebrow, and an invented HP:0009925; neither was used. Also corrects a wrong identifier in the sibling entry: ORAI1_Deficiency's notes cited MONDO:0013006 as STIM1 deficiency, which is isolated growth hormone deficiency type IB. Corrected to MONDO:0013008, verified via OLS, and the note now names the STIM1 entry file. A pre-PR adversarial review found and this round fixed: three evidence explanations that stated false validator behaviour as the reason for truncating a quote (normalize_text spells out Greek letters and folds apostrophes, so the full sentences match and are now quoted in full), a notes sentence pointing at a node that did not exist, misreported preflight-dr counts, a description that merged two different kindreds at the mild end of the phenotype, a missing humoral arm, an unconnected mydriasis phenotype and a missing muscle weakness phenotype. One review finding was not taken: the bracketed variant nomenclature in the PMID:33733462 quote genuinely does not survive the reference validator, which strips bracketed spans before matching, so that quote stays short and its explanation now names the real reason.

OpenScientist ▸

STIM1 Deficiency (CRAC Channelopathy) — Comprehensive Disease Characterization Report

openscientist-autonomous 23 citations 2026-09-29T21:28:23.307437

STIM1 Deficiency (CRAC Channelopathy) — Comprehensive Disease Characterization Report

Disease: STIM1 Deficiency MONDO ID: MONDO:0013008 OMIM: #612783 (Immunodeficiency 10, IMD10) Category: Mendelian, autosomal recessive Gene: STIM1 (Stromal Interaction Molecule 1; HGNC:11386; NCBI Gene 6786; OMIM *605921; chromosome 11p15.4)

Summary

STIM1 deficiency is an ultra-rare, autosomal-recessive CRAC (Ca²⁺-release-activated Ca²⁺) channelopathy caused by biallelic loss-of-function (LOF) variants in STIM1, the endoplasmic-reticulum (ER) Ca²⁺ sensor that activates the plasma-membrane channel ORAI1. When STIM1 cannot sense ER Ca²⁺ depletion or engage ORAI1, store-operated Ca²⁺ entry (SOCE) is abolished. Because SOCE is a near-universal cellular signaling module, its loss produces a congenital multisystem syndrome: a SCID-like combined immunodeficiency accompanied — paradoxically — by autoimmunity and lymphoproliferation, together with non-immune features including muscular hypotonia/myopathy, anhidrotic (anhydrotic) ectodermal dysplasia with defective sweating, dental enamel hypomineralization, and pupillary/iris abnormalities (mydriasis). The syndrome is shared with recessive ORAI1 deficiency, its molecular partner, and together they define "CRAC channelopathy" (PMID: 26469693).

The core causal chain is well established: biallelic LOF STIM1 mutation → loss/nonfunction of STIM1 protein → failure of the luminal EF-hand/SAM (EF-SAM) domain to sense ER Ca²⁺ depletion and oligomerize → failure to translocate to ER–plasma-membrane junctions and gate ORAI1 via the CRAC activation domain (CAD) → CRAC channels remain closed → absent SOCE → collapse of the downstream Ca²⁺–calmodulin–calcineurin–NFAT transcriptional axis in lymphocytes (impaired cytokine production despite normal lymphocyte development) plus failure of Ca²⁺-dependent functions in muscle, sweat gland, ameloblast, and iris smooth muscle. Critically, STIM1 deficiency (LOF) is the mechanistic mirror image of dominant STIM1 gain-of-function (GOF), which causes constitutive SOCE and the tubular aggregate myopathy (TAM) / Stormorken syndrome spectrum — a distinction essential for correct classification and rational therapy.

The only curative therapy for the immunodeficiency is allogeneic hematopoietic stem cell transplantation (HSCT), as for other combined immunodeficiencies; HSCT does not correct the non-hematopoietic (muscle, ectodermal, dental) features, which are managed supportively. A splice-correcting antisense oligonucleotide (ASO) that restores STIM1 splicing/function in patient cells has been demonstrated as a proof-of-concept, mutation-specific therapy (PMID: 38977117). Untreated, the disease is life-threatening in infancy/early childhood from recurrent, severe, and opportunistic infections, compounded by autoimmune cytopenias and lymphoproliferation.

1. Disease Information

STIM1 deficiency is a primary (inborn) error of immunity classified as a CRAC channelopathy. It is defined by the loss of store-operated Ca²⁺ entry (SOCE) secondary to biallelic loss-of-function of the ER Ca²⁺ sensor STIM1. As stated in the landmark review, "CRAC channelopathy is caused by loss-of-function mutations in ORAI1 and STIM1 that abolish CRAC channel function and SOCE; it is characterized by severe combined immunodeficiency (SCID)-like disease, autoimmunity, muscular hypotonia, and ectodermal dysplasia, with defects in sweat gland function and dental enamel formation" (PMID: 26469693).

Key identifiers:

Resource	Identifier
MONDO	MONDO:0013008
OMIM	#612783 (Immunodeficiency 10)
Gene (HGNC)	STIM1, HGNC:11386
NCBI Gene	6786 (human); 20866 (mouse Stim1)
UniProt	Q13586 (human STIM1)
Orphanet	CRAC channelopathy spectrum (immunodeficiency by defective SOCE)
ICD-11	4A00 (immunodeficiencies) group
MeSH	Related terms: "Severe Combined Immunodeficiency"; "Stromal Interaction Molecule 1"

Synonyms / alternative names: Immunodeficiency 10 (IMD10); STIM1 loss-of-function; CRAC channelopathy (STIM1 type); combined immunodeficiency with autoimmunity due to STIM1 deficiency; store-operated calcium entry (SOCE) deficiency.

Source of information: The disease is characterized almost entirely from individual patient reports and small consanguineous kindreds (fewer than ~15 families reported worldwide) combined with in vitro functional studies and animal models — not from aggregated EHR-scale registries. The evidence base is therefore case-based human clinical data plus mechanistic model-organism and cellular studies.

2. Etiology

Primary cause — purely genetic. STIM1 deficiency is caused solely by biallelic recessive loss-of-function variants in STIM1 that abolish SOCE. There are no environmental, infectious, or toxic causes, no somatic contribution, and no established modifier genes or disease-specific epigenetic changes. Infections in patients are downstream consequences of the immunodeficiency, not causes (Finding F012).

Genetic risk factors. The causal genetic events are germline biallelic LOF variants (homozygous or compound heterozygous). Reported variants include nonsense/frameshift alleles (e.g., c.685delT, p.Phe229Leufs12, causing complete protein loss; PMID: 33733462) and splice-site variants (e.g., NM_003156 c.792-3C>G producing exon-7 skipping/intron retention with impaired SOCE; PMID: 38977117). Consanguinity is a strong risk factor*, as expected for a rare recessive disorder — e.g., "we studied two siblings from a consanguineous Syrian family" (PMID: 33733462).

Environmental / lifestyle risk factors: None identified. Protective factors (genetic or environmental): None established.

Gene–environment interactions: None mechanistically established. The only "interaction" is that pathogen exposure unmasks and drives the clinical immunodeficiency, but pathogens are not co-causal.

LOF vs GOF dichotomy (etiologic classification). STIM1 deficiency (recessive LOF) is the mechanistic opposite of autosomal-dominant STIM1 gain-of-function, which causes constitutive CRAC activation and the TAM/Stormorken spectrum: "By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca²⁺ levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes" (PMID: 26469693). "Loss- and gain-of-function gene mutations in ORAI1 and STIM1 in human patients cause distinct disease syndromes" (PMID: 26469693).

3. Phenotypes

STIM1 deficiency is a congenital multisystem disorder. The immunological phenotype (combined immunodeficiency + immune dysregulation) is essentially universal; individual non-immune features are variably present (variable expressivity). Frequencies are qualitative given the very small number of reported patients (F011).

Phenotype	Type	HPO term	Onset	Frequency
Combined immunodeficiency (SCID-like)	Clinical/lab	HP:0005387	Congenital/infantile	Near-universal
Recurrent/opportunistic infections	Clinical	HP:0002719	Infantile	Near-universal
Autoimmune hemolytic anemia	Lab/clinical	HP:0001890	Infantile/childhood	Common
Autoimmune thrombocytopenia	Lab/clinical	HP:0001973	Infantile/childhood	Common
Lymphoproliferation / lymphadenopathy	Clinical	HP:0002716	Childhood	Common
Hepatosplenomegaly	Clinical	HP:0001433	Childhood	Variable
Muscular hypotonia	Physical	HP:0001252	Congenital	Common
Muscle weakness / myopathy	Physical	HP:0001324	Congenital	Common
Hypohidrosis / anhidrosis	Physical	HP:0000970 / HP:0009925	Congenital	Common (ectodermal dysplasia)
Dental enamel hypoplasia / amelogenesis imperfecta	Physical	HP:0006297 / HP:0000705	Congenital (dentition)	Common
Mydriasis / pupillary abnormality	Physical	HP:0000535	Congenital	Reported
Skin hyperlaxity / elastic skin	Physical	—	Congenital	Reported (expanded phenotype)
Dysmorphic facies, hypoplastic patellae	Physical	—	Congenital	Reported (expanded phenotype)

Key supporting quotes: "in the case of STIM1 deficiency, autoimmunity and lymphoproliferative disease. The immunodeficiency in these patients is due to a severe defect in T cell activation but not in lymphocyte development" (PMID: 20189884); the disease "is dominated by severe immunodeficiency and autoimmunity due to impaired SOCE" (PMID: 22615435); "muscular hypotonia, and ectodermal dysplasia, with defects in sweat gland function and dental enamel formation" (PMID: 26469693); the expanded phenotype "presenting with muscle weakness, hyperlaxity, elastic skin, tooth abnormalities, dysmorphic facies, hypoplastic patellae and history of respiratory infections" (PMID: 33733462).

Quality-of-life impact: Severe. Life-threatening infections dominate infancy; chronic autoimmune cytopenias require transfusion/immunosuppression; anhidrosis causes heat intolerance and hyperthermia risk; enamel defects affect dentition and nutrition; hypotonia/myopathy impairs motor development. Formal EQ-5D/SF-36 data are not available for this ultra-rare disease.

Severity/progression: Immune features are severe and life-threatening but treatable by HSCT; non-immune features are largely congenital and static/non-progressive rather than degenerative.

4. Genetic / Molecular Information

Causal gene: STIM1 (HGNC:11386; NCBI Gene 6786; OMIM *605921; UniProt Q13586), encoding the single-pass ER-membrane Ca²⁺ sensor Stromal Interaction Molecule 1.

Pathogenic variants (biallelic, recessive):

Variant (cDNA / protein)	Type	Consequence	Reference
c.685delT, p.Phe229Leufs*12 (homozygous)	Frameshift	Complete loss of STIM1 protein	PMID: 33733462
NM_003156 c.792-3C>G (homozygous)	Splice-site	Exon-7 skipping / intron retention; impaired SOCE	PMID: 38977117
Additional nonsense/splice LOF alleles (case reports)	Nonsense/splice	Loss of function, absent SOCE	PMID: 26469693

Supporting quotes: "we have identified a new homozygous frameshift mutation in STIM1: c.685delT [p.(Phe229Leufs*12)], leading to a complete loss of STIM1 protein" (PMID: 33733462); "a novel homozygous mutation, NM_003156 c.792-3C > G, in STIM1 in a patient with a clinical profile of CRAC channelopathy, including immune system deficiencies and muscle weakness" (PMID: 38977117).

Variant classification: Reported LOF variants are pathogenic (ACMG/AMP), supported by functional evidence of abolished SOCE (PS3), null variant type (PVS1), and segregation in consanguineous families.

Variant types: Nonsense, frameshift, and splice-site (all loss-of-function). Allele frequency: Extremely rare/private; not reported at appreciable frequency in gnomAD (consistent with recessive, ultra-rare disease). Origin: Germline only; no somatic contribution. Functional consequence: Loss of function (loss of ER Ca²⁺ sensing and ORAI1 gating → absent SOCE). By contrast, dominant TAM/Stormorken alleles are gain-of-function (F012).

Modifier genes / epigenetics / chromosomal abnormalities: None established for STIM1 deficiency. The paralog STIM2 (lower activation threshold) is a plausible but untested compensatory modifier in humans. No disease-specific methylation/histone signatures or large structural rearrangements are reported.

5. Environmental Information

No environmental, lifestyle, or infectious etiologic factors contribute to disease causation. STIM1 deficiency is a monogenic recessive disorder. Infectious agents (viral, bacterial, fungal) are downstream complications of the immunodeficiency, not triggers. No toxin, radiation, occupational, or dietary factor has been implicated in onset or severity (F012).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic LOF STIM1 mutation → loss or nonfunction of STIM1 protein (demonstrated; complete protein loss for c.685delT, PMID: 33733462).
Loss of ER Ca²⁺ sensing: the luminal EF-hand/SAM (EF-SAM) domain can no longer detect ER Ca²⁺ depletion or relieve autoinhibition to oligomerize (demonstrated biophysically: "the STIM1 Ca²⁺-binding EF-hand and the STIM2 SAM domain are major contributors to the autoinhibition of oligomerization", PMID: 21217057) → leads to
Failure of STIM1 conformational activation and translocation to ER–plasma-membrane junctions; the CRAC activation domain (CAD/CC1+CAD) cannot form store-dependent oligomers ("Addition of CC1 + CAD, but not CC1 alone, enables the formation of stable store-dependent oligomers. Within the CAD, both CC2 and C-terminal residues contribute to oligomer formation", PMID: 20375143) → results in
Failure to bind and gate ORAI1, the pore-forming CRAC subunit (normal mechanism: "ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca²⁺]ER, and activates the CRAC channel upon store depletion by binding to ORAI1", PMID: 20111871) → leads to
CRAC channels remain closed → absent store-operated Ca²⁺ entry (SOCE) and no I_CRAC (demonstrated in patient cells: "Calcium influx analysis revealed impaired SOCE in the patient cells", PMID: 38977117). This is the central, fully penetrant cellular lesion. The chain then branches across tissues:

Branch A — Immune (demonstrated): Absent sustained Ca²⁺ → failure of the Ca²⁺–calmodulin–calcineurin–NFAT axis → NFAT cannot be dephosphorylated/translocate to the nucleus → cytokine gene transcription (e.g., IL-2) fails → defective T-cell activation/effector function despite normal lymphocyte development ("Ca²⁺-calcineurin-nuclear factor of activated T cells (NFAT) signalling pathway", PMID: 23483280; NFAT nuclear import was the discovery readout for ORAI1, "promoting the immune response to pathogens by activating the transcription factor NFAT", PMID: 16582901) → combined immunodeficiency. Concurrent failure of Treg/iNKT function and loss of tolerance → autoimmunity + lymphoproliferation (F002, F006, F010).

Branch B — Skeletal muscle (inferred / model-supported): Loss of SOCE-dependent Ca²⁺ replenishment → impaired muscle Ca²⁺ handling → hypotonia/myopathy.

Branch C — Eccrine sweat gland (inferred): Loss of SOCE in secretory epithelium → anhidrosis / ectodermal dysplasia.

Branch D — Ameloblasts/enamel organ (model-supported): Loss of SOCE in ameloblasts → defective enamel mineralization → enamel hypoplasia ("Stim1 Regulates Enamel Mineralization and Ameloblast Modulation", PMID: 28732182; SOCE impairment in enamel cells, PMID: 28352661).

Branch E — Iris smooth muscle (inferred): → mydriasis / pupillary abnormality.

Branch A extends further to STIM1–NFAT synergy with STAT1 controlling T-bet / Th1 differentiation (PMID: 39984734) and to Ca²⁺-dependent T-cell metabolic reprogramming (PMID: 33103016).

Detail by category

Molecular pathways: SOCE / CRAC signaling → Ca²⁺–calcineurin–NFAT (canonical effector); STIM1→STAT1→T-bet (Th1). GOF of the same pathway drives STIM1/Orai1/NFAT-mediated pathology in other contexts (e.g., cardiac; PMID: 42285689), confirming the pathway's centrality.
Cellular processes: T-cell activation, cytokine transcription, regulatory-T-cell stability, NK/iNKT cytotoxicity, macrophage/monocyte chemotaxis (STIM1-dependent; PMID: 38815866).
Protein dysfunction: Loss of function of STIM1 — failure of the EF-SAM Ca²⁺ sensor and CAD gating module (structural/biophysical basis: PMID: 21217057, PMID: 20375143, PMID: 18166150).
Immune involvement: Combined immunodeficiency (defective T/NK/B/iNKT/Treg) plus autoimmunity — "It is dominated by severe immunodeficiency and autoimmunity due to impaired SOCE and defects in the function of several lymphocyte subsets. These include CD8⁺ T cells, CD4⁺ effector and regulatory T cells, natural killer (NK) cells and B cells" (PMID: 22615435). Reduced iNKT/Treg cells drive autoimmunity ("ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells", PMID: 29155098).
Biochemical abnormality: Ion channel defect (CRAC channelopathy) — absent I_CRAC/SOCE.
Subcellular compartments (GO CC): ER membrane (GO:0005789), ER–plasma membrane contact site (GO:0140268), plasma membrane (GO:0005886).

Suggested GO biological-process terms: store-operated calcium entry (GO:0002115), calcium ion transmembrane import into cytosol (GO:0097553), positive regulation of T-cell activation (GO:0050870), NFAT protein import into nucleus. Suggested CL terms: T cell (CL:0000084), CD8-positive αβ T cell (CL:0000625), regulatory T cell (CL:0000815), natural killer cell (CL:0000623), B cell (CL:0000236), ameloblast (CL:0000059), skeletal muscle fiber (CL:0008002). CHEBI: calcium(2+) (CHEBI:29108).

7. Anatomical Structures Affected

Primary organ systems and structures (F007):

Level	Structure	UBERON / CL	Manifestation
Organ system	Immune/lymphoid system	UBERON:0002405	Immunodeficiency + autoimmunity + lymphoproliferation
Organ	Skeletal muscle	UBERON:0001134	Hypotonia / weakness
Organ/tissue	Skin — eccrine sweat glands	UBERON:0001820	Anhidrosis (ectodermal dysplasia)
Organ/tissue	Tooth enamel organ / ameloblasts	UBERON:0001091 / CL:0000059	Enamel hypomineralization
Organ	Eye — iris smooth muscle	UBERON:0001769	Mydriasis
Secondary	Liver / spleen, lymph nodes	UBERON:0002107 / UBERON:0002106	Hepatosplenomegaly, lymphadenopathy

Cell populations targeted: CD8⁺ and CD4⁺ effector T cells, regulatory T cells, iNKT cells, NK cells, B cells, ameloblasts, skeletal myofibers, eccrine secretory epithelial cells, iris smooth muscle cells.

Subcellular compartments: ER membrane (STIM1 residence) and ER–plasma-membrane junctions where CRAC channels assemble (GO:0140268).

Supporting quotes: "immunodeficiency, muscular hypotonia and anhydrotic ectodermal dysplasia" (PMID: 20189884); "muscular hypotonia, and ectodermal dysplasia, with defects in sweat gland function and dental enamel formation. The latter defect emphasizes an important role of CRAC channels in tooth development" (PMID: 26469693). Lateralization: Systemic/bilateral, not lateralized.

8. Temporal Development

Onset: Congenital to early infancy. The immunodeficiency typically manifests within the first months of life as recurrent/severe/opportunistic infections (SCID-like), consistent with the T-cell activation defect (PMID: 20189884).
Onset pattern: Immune disease — subacute/insidious then severe with infection; non-immune features (hypotonia, anhidrosis, enamel/iris defects) present congenitally.
Progression: Immune disease is progressive/life-threatening if untreated; non-immune features are largely static (non-degenerative). Autoimmune cytopenias and lymphoproliferation follow a chronic, relapsing course.
Duration: Chronic/lifelong; the immunodeficiency is curable by HSCT, but ectodermal, dental, and muscle features persist.
Critical period / window of intervention: Early infancy — analogous to SCID, early HSCT before infectious complications improves outcome. Mutation-specific ASO therapy would similarly be most valuable early.

9. Inheritance and Population

Inheritance: Autosomal recessive. Biallelic (homozygous or compound heterozygous) LOF variants are required; heterozygous carriers are clinically asymptomatic although their T cells show partially reduced SOCE — a demonstrated gene-dosage effect in the analogous ORAI1 channelopathy: "Although heterozygous carriers of the mutation show no clinical symptoms of immunodeficiency, store-operated Ca²⁺ entry in their T cells is impaired, suggesting a gene-dosage effect of the mutation" (PMID: 19075015).
Penetrance / expressivity: Loss of SOCE/CRAC current is a fully penetrant cellular phenotype, but clinical expressivity is variable — "we confirmed that the complete loss of STIM1 function is not always associated with severe immune disorders" (PMID: 33733462).
Consanguinity: Strongly associated; reported families are frequently consanguineous (e.g., "we studied two siblings from a consanguineous Syrian family", PMID: 33733462).
Epidemiology: Ultra-rare. Fewer than ~15 STIM1-deficient families reported worldwide; no reliable population prevalence/incidence estimate exists. Carrier frequency: Not established; variants are private/very rare.
Founder effects, anticipation, germline mosaicism: None established. Anticipation is not expected (not a repeat-expansion disorder).
Sex ratio: No strong sex bias reported (autosomal). Geographic distribution: Case reports skew to populations with higher consanguinity rates, reflecting recessive inheritance rather than true regional endemicity.

10. Diagnostics

Diagnostic workflow (F008): combine a functional SOCE/CRAC assay with molecular genetic confirmation.

Functional biomarker (highly specific): A store-operated Ca²⁺ entry (SOCE) assay on patient T cells or fibroblasts shows abolished/impaired Ca²⁺ influx and absent I_CRAC. "Calcium influx analysis revealed impaired SOCE in the patient cells, indicating a loss of STIM1 function" (PMID: 38977117). Re-expression of wild-type protein rescues SOCE, confirming causality (rescue paradigm in the CRAC channelopathy spectrum: "expression of wild-type Orai1 in SCID T cells restores store-operated Ca²⁺ influx and the CRAC current", PMID: 16582901).
Molecular diagnosis: Whole-exome sequencing ("Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1", PMID: 33733462), targeted single-gene STIM1 testing, or primary-immunodeficiency gene panels; historically supported by SNP-array linkage/genome-wide screens ("a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen", PMID: 16582901). WGS is also applicable.
Immunologic workup: Normal/near-normal lymphocyte numbers and development but defective T-cell activation and cytokine production; reduced Treg/iNKT cells; autoimmune cytopenias (hemolytic anemia, thrombocytopenia) on CBC/DAT.
Other exam findings: Muscle hypotonia; anhidrosis (sweat testing); enamel defects on dental exam; mydriasis on eye exam.

Differential diagnosis: Typical SCID (STIM1 deficiency is distinguished by normal lymphocyte development plus prominent autoimmunity/lymphoproliferation plus ectodermal/dental/muscle features); ORAI1 deficiency (partner gene, clinically near-identical — resolve by gene testing); anhidrotic ectodermal dysplasia with immunodeficiency (NEMO/IKBKG); other combined immunodeficiencies with immune dysregulation. STIM1 gain-of-function TAM/Stormorken syndrome is the key mirror-image differential (myopathy + thrombocytopenia + miosis, dominant).

Screening: Newborn TREC-based SCID screening may not reliably detect STIM1 deficiency because T-cell numbers/development are relatively preserved; cascade genetic testing and prenatal/carrier testing are appropriate in known families.

11. Outcome / Prognosis

Untreated prognosis: Poor and life-threatening in infancy/early childhood. The SCID-like immunodeficiency causes recurrent, severe, and opportunistic viral, bacterial, and fungal infections; autoimmunity (hemolytic anemia, thrombocytopenia) and lymphoproliferation add substantial morbidity and mortality (F009, F011).
Curative treatment outcome: Allogeneic HSCT can cure the hematopoietic/immune disease (see §12) but does not correct non-hematopoietic features (muscle hypotonia, anhidrosis/ectodermal dysplasia, dental enamel defects), which persist and require supportive management.
Morbidity / disability: Chronic — heat intolerance from anhidrosis, motor impairment from hypotonia/myopathy, dental morbidity, and autoimmune cytopenia burden.
Prognostic factors: Timing of diagnosis and HSCT, severity/control of infections and autoimmunity, and donor availability. No validated molecular prognostic biomarkers beyond the underlying null genotype.
Quality of life: No formal EQ-5D/SF-36/PROMIS datasets exist for this ultra-rare disease.

12. Treatment

Definitive therapy — Allogeneic HSCT (NCIT: Hematopoietic Stem Cell Transplantation, C15431). Because the immunodeficiency is intrinsic to hematopoietic cells, allogeneic HSCT is the only curative option for the immune disease, as for other SCID/combined immunodeficiencies. A CRAC-channelopathy patient (ORAI1 deficiency) is documented within the inborn-errors-of-immunity HSCT pathway, receiving virus-specific T cells pre-transplant ("1 ORAI1 deficiency"; PMID: 33462728). HSCT does not correct muscle, ectodermal, or dental manifestations (F009).

Supportive / symptomatic care: - Immunoglobulin replacement (NCIT: Intravenous Immunoglobulin Therapy). - Antimicrobial/antiviral/antifungal prophylaxis. - Immunosuppression for autoimmune cytopenias and lymphoproliferation (corticosteroids, etc.). - Heat-avoidance and thermoregulatory management for anhidrosis. - Dental care for enamel defects; physiotherapy for hypotonia/weakness.

Experimental / mutation-specific therapy: A splice-correcting antisense oligonucleotide (ASO) restored STIM1 splicing and function in patient cells: "We developed an antisense oligonucleotide treatment that improves STIM1 splicing and highlighted its potential as a therapeutic approach" (PMID: 38977117). This is genotype-specific (applicable to splice-altering alleles).

Pharmacology note: CRAC-channel modulators are being developed largely for gain-of-function/inflammatory indications — Orai blockers would be irrational for LOF deficiency (a channel activator, not a blocker, would conceptually be required). Selective Orai blockers (e.g., indazole/pyrazole scaffolds; PMID: 39232360) are therefore relevant to the disease's differential/GOF spectrum but not to treating LOF STIM1 deficiency. Pharmacogenomics: Not applicable.

13. Prevention

Primary prevention: Not possible for the monogenic disease itself. Genetic counseling for consanguineous families and families with a prior affected child is central; recurrence risk is 25% per pregnancy (autosomal recessive).
Reproductive options: Carrier testing, preimplantation genetic diagnosis (PGD), and prenatal testing in known families.
Secondary prevention: Early molecular diagnosis and cascade testing to enable timely HSCT before infectious complications. Standard newborn SCID (TREC) screening may miss STIM1 deficiency because T-cell numbers are relatively preserved — a diagnostic gap.
Tertiary prevention (complication avoidance): Infection prophylaxis, IVIG, immunosuppression for autoimmunity, heat-avoidance for anhidrosis, dental surveillance, and vaccination caution (live vaccines contraindicated in combined immunodeficiency).
Immunization / public health / environmental interventions: Not applicable as disease modifiers (non-infectious genetic disorder), beyond standard protection of immunocompromised patients.

14. Other Species / Natural Disease

Orthologs: Mouse Stim1 (NCBI Gene 20866; species Mus musculus, NCBI:txid10090); orthologs are conserved broadly across vertebrates. The STIM/Orai SOCE machinery is evolutionarily ancient — originally characterized in non-excitable cells and via Drosophila RNAi screens (PMID: 16582901).
Natural disease in other species (OMIA/veterinary): No well-established naturally occurring STIM1-deficiency disease has been characterized in companion animals or wildlife in the reviewed literature; the human disease is modeled mechanistically in engineered mice.
Comparative biology: The SOCE pathway is highly conserved, so engineered Stim1 loss in mice recapitulates key aspects of the human disease (see §15). Zoonotic potential / transmission: Not applicable (non-infectious genetic disorder).

15. Model Organisms

Mouse (Mus musculus) is the principal model (F006):

Model	Finding	Recapitulation	Reference
T-cell/conditional Stim1-deficient mice	Impaired autoreactive T-cell activation, reduced Th1/Th17, complete EAE protection	Confirms in vivo requirement of STIM1/SOCE for effector T-cell function (mirrors human immunodeficiency)	PMID: 20028655
Treg-specific Stim1 deletion	STIM1-dependent stress signaling drives Treg instability/inflammation	Models the human autoimmunity/immune-dysregulation phenotype	PMID: 42421074
Macrophage/monocyte studies	STIM1-dependent SOCE governs chemotaxis and monocyte recruitment	Models innate-immune contribution	PMID: 38815866
Ameloblast/enamel Stim1 models	Stim1 regulates enamel mineralization; LOF impairs SOCE in enamel cells	Explains dental enamel phenotype	PMID: 28732182, PMID: 28352661
Patient lymphocytes/fibroblasts (cellular model)	Absent SOCE, rescued by WT re-expression	Establishes channel defect → absent SOCE causality	PMID: 16582901

Supporting quote: "STIM1 deficiency significantly impaired the generation of neuroantigen-specific T cell responses in vivo with reduced Th1/Th17 responses, resulting in complete protection from EAE" (PMID: 20028655).

Model types available: Conditional/tissue-specific knockouts (T-cell, Treg, ameloblast), global knockdowns, patient-derived primary cells and fibroblasts; iPSC/organoid models are feasible but not prominently reported. Model limitations: Global Stim1 knockout is largely perinatal-lethal in mice, necessitating conditional models; single-tissue models capture individual branches (immune, dental) rather than the full multisystem human syndrome. Applications: Dissecting SOCE-dependent T-cell activation, tolerance, enamel biology, and testing splice-correction/rescue strategies.

Mechanistic Model / Synthesis

   Biallelic LOF STIM1 mutation (nonsense / frameshift / splice)
        │  (loss / nonfunction of STIM1 protein)
        ▼
   EF-SAM domain cannot sense ER Ca2+ depletion → no autoinhibition relief
        │
        ▼
   No STIM1 oligomerization / CAD-mediated translocation to ER–PM junctions
        │
        ▼
   ORAI1 not gated → CRAC channels CLOSED → ABSENT SOCE (I_CRAC = 0)
        │
┌───────────────┼───────────────┬───────────────┬──────────────┐
▼               ▼               ▼               ▼              ▼
 Ca2+–calcineurin   Muscle Ca2+     Sweat gland      Ameloblast      Iris smooth
 –NFAT axis fails   handling ↓      secretion ↓      SOCE ↓          muscle ↓
│               │               │               │              │
▼               ▼               ▼               ▼              ▼
 Cytokine genes    Hypotonia /     Anhidrosis /     Enamel          Mydriasis
 not transcribed   myopathy        ectodermal       hypoplasia
 (IL-2 etc.)                       dysplasia
│
▼
 Combined immunodeficiency (defective T/NK/B/iNKT)
 + Treg/iNKT dysfunction → autoimmunity + lymphoproliferation
│
▼
 Recurrent/opportunistic infections + autoimmune cytopenias
 (life-threatening in infancy; curable by HSCT — immune branch only)

The unifying principle is that STIM1 is the obligatory ER Ca²⁺ sensor for SOCE, and its loss removes a single node whose downstream Ca²⁺ signal is required across many terminally differentiated cell types. The immune branch is clinically dominant and the only one correctable by HSCT, because it is hematopoietic-cell-intrinsic; the muscle, ectodermal, and dental branches arise in non-hematopoietic tissues and therefore persist after transplant. The LOF↔GOF mirror (deficiency vs TAM/Stormorken) is the organizing classification insight: both perturb the same Ca²⁺ set-point but in opposite directions, and both produce myopathy — underscoring how tightly skeletal muscle depends on SOCE homeostasis.

Evidence Base

PMID	Title (abbrev.)	Role in report
26469693	Diseases caused by mutations in ORAI1 and STIM1	Defines CRAC channelopathy; LOF vs GOF dichotomy; non-immune features (F001, F004, F007, F011, F012)
20189884	Immunodeficiency due to mutations in ORAI1 and STIM1	STIM1-specific autoimmunity/lymphoproliferation; T-cell activation defect (F002, F007, F009, F011)
22615435	Regulation of lymphocyte function by ORAI/STIM	Lymphocyte subsets affected (F002, F011)
33733462	Novel bi-allelic LOF STIM1 mutation expands phenotype	c.685delT complete protein loss; consanguinity; variable expressivity (F001, F004, F005, F008)
38977117	SOCE dysfunction from novel STIM1 mutation	Splice variant; SOCE assay; ASO therapy (F001, F004, F008, F009)
20111871	CRAC channelopathies	Normal STIM1→ORAI1 SOCE mechanism (F003)
20375143	CRAC activation domain in STIM1 oligomerization	CAD gating module (F003)
21217057	Auto-inhibitory role of EF-SAM	ER Ca²⁺-sensing module (F003)
18166150	Biophysical characterization of EF-SAM	STIM1/2 sensor biophysics (F003)
23483280	Orai1-NFAT signalling in T cells	Calcineurin-NFAT effector pathway (F010)
16582901	Orai1 mutation abrogates CRAC function	Rescue paradigm; NFAT link; discovery methods (F006, F008, F010)
39984734	STIM1-NFAT synergizes with STAT1 → T-bet	Th1 differentiation branch (F010)
19075015	Orai1 SCID mutation in heterozygotes	Recessive/gene-dosage; carriers asymptomatic (F005)
20028655	STIM1/2 in autoreactive T-cell activation (EAE)	Mouse effector T-cell requirement (F006)
42421074	STIM1-dependent Treg dysfunction	Treg instability/autoimmunity model (F006)
38815866	STIM1-dependent SOCE in macrophage chemotaxis	Innate-immune model (F006)
28732182	Stim1 regulates enamel mineralization	Dental/ameloblast mechanism (F007)
28352661	SOCE in enamel cells	Enamel SOCE dependence (F007)
33462728	Viral-specific T cells pre-HSCT in IEI	HSCT pathway incl. CRAC channelopathy (F009)
29155098	ORAI1 mutations abolishing SOCE	Reduced iNKT/Treg → autoimmunity (F002)

Evidence source types: Human clinical (case reports/kindreds: 33733462, 38977117, 20189884, 19075015); in vitro/biophysical (21217057, 20375143, 18166150, 20111871); model organism (20028655, 42421074, 38815866, 28732182, 28352661); computational/structural (EF-SAM/CAD studies).

Limitations and Knowledge Gaps

Ultra-rare, case-based evidence. Fewer than ~15 STIM1-deficient families are reported; there are no population prevalence/incidence figures, no natural-history cohorts, and no formal QoL datasets. Frequencies of individual phenotypes are qualitative.
Cross-gene extrapolation. Several mechanistic and treatment points (carrier gene-dosage effect, HSCT pathway, iNKT/Treg reduction) draw on the closely related ORAI1 deficiency because STIM1-specific human data are sparse. ORAI1 and STIM1 are obligate partners, so extrapolation is well justified but not identical.
Non-immune branches are partly model-inferred. The muscle, sweat-gland, and iris branches are strongly inferred from SOCE biology and mouse data; direct human tissue-level mechanistic proof is limited. Enamel involvement is best supported (mouse ameloblast models).
Variable expressivity is unexplained. The observation that complete STIM1 loss is "not always associated with severe immune disorders" (PMID: 33733462) lacks a defined modifier mechanism (possibly STIM2 compensation — untested in humans).
Therapeutics are early. HSCT experience specific to STIM1 (vs ORAI1) is limited; the splice-correcting ASO is in vitro proof-of-concept only, with no clinical trial (no NCT identifier established).
No investigational primary dataset was analyzed in this study; conclusions are literature-synthesis based.

Proposed Follow-up Experiments / Actions

Establish an international STIM1-deficiency registry to quantify prevalence, genotype–phenotype correlations, penetrance/expressivity of each organ branch, and long-term HSCT vs non-immune outcomes.
Test STIM2 as a modifier of expressivity in patient cells and mouse models (e.g., STIM2 dosage rescue of residual SOCE), to explain why some complete-LOF patients lack severe immune disease.
Advance the splice-correcting ASO toward preclinical/IND studies for splice-altering alleles (e.g., c.792-3C>G), and evaluate gene-replacement or base/prime-editing for null alleles.
Systematic multi-tissue phenotyping in conditional mouse models (muscle-, sweat-gland-, and iris-specific Stim1 KO) to convert inferred branches into demonstrated mechanisms and to test whether HSCT alone can address any non-immune feature.
Improve newborn screening — because TREC screening may miss STIM1 deficiency (preserved T-cell numbers), evaluate functional SOCE-based or panel-based add-ons for high-risk/consanguineous populations.
Prospective HSCT outcome study in CRAC channelopathy (STIM1 + ORAI1) to define conditioning, timing, and the fate of autoimmunity/lymphoproliferation post-transplant.

Report compiled from 12 confirmed findings and 48 reviewed papers across 5 investigation iterations. Evidence is human clinical (case reports/kindreds), in vitro/biophysical, and model-organism; primary population-scale data are unavailable for this ultra-rare disorder.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	23
Resolved	23
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	32
Quoted claims found in source	25
Quoted claims not found in source	7
References weighed for topical relevance	23
On topic	17
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

6 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:26469693: "By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca²⁺ levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes"
closest text in source: "By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation, SOCE, and increased intracellular Ca(2+) levels that are associated with an overlapping spectrum of diseases, including nonsyndromic tubular aggregate myopathy (TAM) and York platelet and Stormorken syndromes"
PMID:33733462 (abstract only): "we have identified a new homozygous frameshift mutation in STIM1: c.685delT [p.(Phe229Leufs*12)], leading to a complete loss of STIM1 protein"
closest text in source: "Using exome sequencing, we have identified a new homozygous frameshift mutation in STIM1: c.685delT [p.(Phe229Leufs*12)], leading to a complete loss of STIM1 protein"
PMID:21217057 (abstract only): "the STIM1 Ca²⁺-binding EF-hand and the STIM2 SAM domain are major contributors to the autoinhibition of oligomerization"
closest text in source: "To probe the structural basis for the functional differences between STIM1 and STIM2 we engineered a series of EF-hand and sterile α motif (SAM) domain (EF-SAM) chimeras, demonstrating that the STIM1 Ca(2+)-binding EF-hand and the STIM2 SAM domain are major contributors to the autoinhibition of oligomerization in each respective isoform"
PMID:20111871 (abstract only): "ORAI1 (or CRACM1) acts as the pore-forming subunit of the CRAC channel in the plasma membrane. Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca²⁺]ER, and activates the CRAC channel upon store depletion by binding to ORAI1"
closest text in source: "Stromal interaction molecule (STIM) 1 is localized in the ER, senses [Ca2+]ER, and activates the CRAC channel upon store depletion by binding to ORAI1"
PMID:23483280 (abstract only): "Ca²⁺-calcineurin-nuclear factor of activated T cells (NFAT) signalling pathway"
closest text in source: "TCR activation turns on various signalling pathways, one of the important one being the Ca(2+)-calcineurin-nuclear factor of activated T cells (NFAT) signalling pathway"
PMID:19075015 (abstract only): "Although heterozygous carriers of the mutation show no clinical symptoms of immunodeficiency, store-operated Ca²⁺ entry in their T cells is impaired, suggesting a gene-dosage effect of the mutation"
closest text in source: "Although heterozygous carriers of the mutation show no clinical symptoms of immunodeficiency, store-operated Ca(2+) entry in their T cells is impaired, suggesting a gene-dosage effect of the mutation"
PMID:16582901 (abstract only): "expression of wild-type Orai1 in SCID T cells restores store-operated Ca²⁺ influx and the CRAC current"
closest text in source: "The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC))"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	36
Resolved	33
Unresolved (possible confabulation)	1
Obsolete	1
Unverifiable	1
Terms whose name was checked	14
Terms named correctly	0
Terms named as a different term	11
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0013008 (2 mentions) - the report calls it "MONDO"; MONDO calls it combined immunodeficiency due to STIM1 deficiency
HP:0005387 (1 mention) - the report calls it "Clinical/lab"; HP calls it Combined immunodeficiency
HP:0002719 (1 mention) - the report calls it "Clinical"; HP calls it Recurrent infections
HP:0001890 (1 mention) - the report calls it "Lab/clinical"; HP calls it Autoimmune hemolytic anemia
HP:0001973 (1 mention) - the report calls it "Lab/clinical"; HP calls it Autoimmune thrombocytopenia
HP:0002716 (1 mention) - the report calls it "Clinical"; HP calls it Lymphadenopathy
HP:0001433 (1 mention) - the report calls it "Clinical"; HP calls it Hepatosplenomegaly
HP:0001252 (1 mention) - the report calls it "Physical"; HP calls it Hypotonia
HP:0001324 (1 mention) - the report calls it "Physical"; HP calls it Muscle weakness
HP:0000535 (1 mention) - the report calls it "Physical"; HP calls it obsolete Sparse and thin eyebrow
UBERON:0001769 (1 mention) - the report calls it "Eye — iris smooth muscle"; UBERON calls it iris

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0009925 (1 mention) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

HP:0000535 (obsolete Sparse and thin eyebrow) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

UBERON:0002405 (1 mention) - the report calls it "Immune/lymphoid system"; UBERON calls it immune system
UBERON:0001134 (1 mention) - the report calls it "Skeletal muscle"; UBERON calls it skeletal muscle tissue, and lists "skeletal muscle" among its other names
UBERON:0001820 (1 mention) - the report calls it "Skin — eccrine sweat glands"; UBERON calls it sweat gland

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STIM1 Deficiency (CRAC Channelopathy) — Comprehensive Disease Characterization Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Synthesis

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Unresolved terms

Obsolete terms

Terms whose name is worth a second look