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Classifications

IUIS Category

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Inheritance

1

Autosomal recessive HP:0000007

Reported patients are homozygous or compound heterozygous for loss-of-function ORAI1 alleles. Heterozygous carriers are clinically unaffected, although their T cells show measurably impaired store-operated calcium entry, indicating a gene-dosage effect at the cellular level that does not reach a clinical threshold.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:16582901 SUPPORT Human Clinical

"The SCID patients are homozygous for a single missense mutation in ORAI1"

Establishes homozygosity for a single ORAI1 allele in the founding kindred, i.e. autosomal recessive inheritance.

PMID:19075015 SUPPORT In Vitro

"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."

Documents that carriers are clinically unaffected while showing a partial cellular phenotype, which is the basis for the recessive classification.

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Mechanistic Hypotheses

1

Canonical SOCE / calcineurin-NFAT Transcriptional Failure Model

canonical_soce_nfat_failure_model CANONICAL

Biallelic ORAI1 loss removes the CRAC channel pore, abolishing store-operated calcium entry; the resulting failure to activate calcineurin leaves NFAT cytoplasmic and the NFAT-dependent cytokine programme uninduced, which produces a functional rather than developmental combined immunodeficiency. The same cellular lesion in skeletal muscle, ameloblasts and sweat gland explains the non-immune arms. This model is supported by the rescue of both SOCE and I_CRAC by wild-type ORAI1 in patient T cells.

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Discussions and Knowledge Gaps

3

Why is the clinical phenotype restricted to lymphocytes, skeletal muscle, ameloblasts and sweat glands when ORAI1 protein is expressed in a wide variety of cell types and organs?

KNOWLEDGE GAP orai1_expression_phenotype_mismatch

Attached to

pathophysiology#Abolished Store-Operated Calcium Entry

Immunohistochemistry in healthy donors shows broad ORAI1 expression, yet the clinical syndrome spares nearly all of those tissues. Either other ORAI paralogues or non-CRAC calcium entry routes compensate outside the affected tissues, or SOCE is simply not rate-limiting there. Which of those it is has not been established, and it matters: it determines whether a systemic CRAC-modulating therapy would have off-target consequences in tissues that look unaffected at baseline.

Does haematopoietic stem cell transplantation, which replaces the lymphoid compartment, leave the myopathy and ectodermal dysplasia untouched over long-term follow-up?

KNOWLEDGE GAP orai1_hsct_non_haematopoietic_arms

Attached to

pathophysiology#Impaired Skeletal Muscle Calcium Handling pathophysiology#Defective Enamel Mineralization

The myopathic, enamel and sweat gland arms are cell-intrinsic to non-haematopoietic tissue, so transplantation should not correct them. The published cohort is too small and follow-up too short for that expectation to have been confirmed, and it is the fact that determines whether transplantation is a cure or only a rescue of the immunological arm.

Is the autoimmunity in ORAI1 deficiency driven by regulatory T cell loss, or by an independent consequence of impaired calcium signalling in B cells and myeloid cells?

KNOWLEDGE GAP orai1_autoimmunity_treg_vs_intrinsic

Attached to

pathophysiology#Autoimmunity

Reduced Treg numbers is the proposed explanation and is the authors' own interpretation, stated as "likely" rather than demonstrated. No experiment has separated the Treg-loss route from a cell-intrinsic tolerance defect elsewhere, and the two would call for different immunomodulatory strategies after transplantation.

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Pathophysiology

11

Biallelic Loss-of-Function ORAI1 Variants

Homozygous or compound heterozygous ORAI1 variants. Reported alleles include the founding p.R91W missense change, frameshift/nonsense alleles (p.A88SfsX25, p.V181SfsX8), and missense alleles p.A103E, p.L194P and p.G98R. Frameshift and several missense alleles abolish ORAI1 protein expression outright; p.R91W leaves protein expressed but non-conducting, so both null and functionally-null genotypes converge on the same cellular phenotype.

ORAI1 hgnc:25896 ⇓ LOSS OF FUNCTION

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

Germline biallelic ORAI1 alleles. Both protein-abolishing (frameshift, nonsense, several missense) and expression-preserving but pore-inactivating (p.R91W) mechanisms are represented.

Downstream

Loss of CRAC Channel Pore Function Absent or non-conducting ORAI1 protein cannot form a functional CRAC channel pore in the plasma membrane.

Show evidence (2 references)

PMID:20004786 SUPPORT Human Clinical

"One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function."

Documents the allelic spectrum and that the variants abolish ORAI1 expression, establishing loss of function as the disease mechanism.

PMID:29155098 SUPPORT Human Clinical

"The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts."

Extends the allelic spectrum and confirms that the variants suppress ORAI1 protein and store-operated calcium entry in patient cells.

Loss of CRAC Channel Pore Function

ORAI1 is the pore-forming subunit of the CRAC channel. Without functional ORAI1, STIM1 has no pore to gate on store depletion, and the CRAC current (I_CRAC) is absent. That ORAI1 is the pore rather than a regulator is established by the rescue experiment: expressing wild-type Orai1 in patient SCID T cells restores both store-operated calcium influx and I_CRAC.

store-operated calcium channel activity GO:0015279 ⇓ LOSS OF FUNCTION

Downstream

Abolished Store-Operated Calcium Entry With no conducting CRAC pore, store depletion no longer produces sustained calcium influx.

Show evidence (1 reference)

PMID:16582901 SUPPORT In Vitro

"expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC))"

The rescue result establishes that loss of ORAI1 is what removes CRAC channel function, rather than a correlated defect.

Abolished Store-Operated Calcium Entry

Store-operated calcium entry is the dominant sustained calcium influx pathway in lymphocytes. Its loss is demonstrable in patient T cells, fibroblasts and other cell types, and is the single cellular lesion from which every downstream arm of the disease follows. Because ORAI1 is expressed almost ubiquitously, 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 ORAI1 is expressed.

T cell CL:0000084 fibroblast CL:0000057

store-operated calcium entry GO:0002115 ↓ DECREASED

Animal models

Orai1 knockout mouse Mouse partially recapitulates The mouse reproduces the underlying loss of ORAI1-dependent store-operated calcium entry, which is the shared upstream lesion.

Downstream

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

Impaired Skeletal Muscle Calcium Handling Loss of SOCE in skeletal muscle fibres, where it contributes to refilling of sarcoplasmic reticulum calcium stores.

Defective Enamel Mineralization Ameloblasts depend on CRAC-mediated calcium influx to supply the calcium used for enamel mineralization.

Hemophagocytic Lymphohistiocytosis HLH has been reported as a presenting manifestation. The route is deliberately left unspecified: HLH is normally understood as a T-cell-driven syndrome, and these patients have a severe defect in lymphocyte activation, so the reporting authors proposed a pathway independent of T- and NK-cell activation rather than a mechanism through the nodes above.

Sweat Gland Secretory Failure Loss of SOCE in sweat gland secretory cells, whose fluid secretion is calcium-dependent.

Show evidence (1 reference)

PMID:20004786 SUPPORT Human Clinical

"In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs."

Establishes the expression/phenotype mismatch that makes SOCE non-redundancy, rather than expression pattern, the explanation for which organs are affected.

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 large NFAT-dependent transcriptional programme — cytokines, chemokines and many other genes required for a productive immune response — 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 Invariant NKT and Regulatory T Cell Numbers Development of iNKT and regulatory T cell lineages is calcium/NFAT-dependent, unlike conventional T cell development.

Show evidence (1 reference)

PMID:17572487 SUPPORT Human Clinical

"the underlying defect in a family with a hereditary severe combined immune deficiency (SCID) syndrome is a defect in CRAC channel function, store-operated Ca(2+) entry, NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential..."

States the full causal chain from CRAC channel failure through NFAT to the transcriptional defect, in the patients themselves.

Impaired T Cell Effector Function

The defining immunological abnormality. T cells are present in normal numbers and develop normally, but fail to produce cytokines and fail to proliferate on stimulation. This is a functional, not a developmental, combined immunodeficiency — the point at which ORAI1 deficiency separates from the classical T-negative severe combined immunodeficiencies.

T cell CL:0000084

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

Downstream

Susceptibility to Severe Infection Loss of T cell effector output leaves the patient unable to control viral, bacterial and fungal pathogens.

Show evidence (1 reference)

PMID:20004786 SUPPORT Human Clinical

"The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes"

States the function-versus-development distinction that defines this node and distinguishes the disease from developmental SCIDs.

Reduced Invariant NKT and Regulatory T Cell Numbers

Beyond the functional defect in conventional T cells, ORAI1-deficient patients have strongly reduced numbers of invariant natural killer T cells and regulatory T cells, and altered composition of gamma-delta T cell and NK cell subsets. Loss of the regulatory compartment is the most plausible route from a calcium-signalling defect to the autoimmunity these patients develop, which is otherwise a counterintuitive feature of an immunodeficiency.

regulatory T cell CL:0000815 ↓ DECREASED

regulatory T cell differentiation GO:0045066 ↓ DECREASED

Downstream

Autoimmunity Depletion of the regulatory T cell compartment removes peripheral tolerance restraint.

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets."

Directly documents the reduced iNKT and Treg compartments in patients.

Susceptibility to Severe Infection

Recurrent and life-threatening infection presenting in infancy, the clinical presentation that brings these patients to attention. Untreated, the immunodeficiency is fatal in early childhood.

Downstream

Combined Immunodeficiency The clinical immunodeficiency phenotype, presenting in infancy with severe infection.

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms."

Establishes combined immunodeficiency, with accompanying autoimmunity and extra-immune features, as the clinical syndrome.

Autoimmunity

Autoimmune cytopenias — haemolytic anaemia and thrombocytopenia — occur in ORAI1-deficient patients alongside the immunodeficiency, and where they occur they are attributed to loss of the regulatory T cell compartment rather than to the effector defect. How often they occur is disputed and the entry does not settle it. The published series up to 2015 record the same single autoimmune patient — 1 of 6 in the 2009 report, which states it covers every ORAI1 patient then known, and 1 of 7 in the 2015 review, whose denominator is those six plus one later patient — and the review calls autoimmunity less common in ORAI1 than in STIM1 deficiency on that basis. Lian 2018 then reported three affected patients in one series. So the disagreement is between an early near-complete census and a later series, not between two independent cohorts. The review itself notes that the small patient numbers and early mortality may censor the observation rather than establish a low rate. The node is retained because the phenomenon is real and mechanistically informative about the Treg compartment, not because it is a recurrent feature of every patient.

Downstream

Autoimmune Hemolytic Anemia Autoimmune destruction of erythrocytes, one of the autoimmune cytopenias reported in CRAC channelopathy.

Show evidence (5 references)

PMID:29155098 SUPPORT Human Clinical

"ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity."

Links the reduced regulatory compartment to the autoimmune phenotype, as the authors' own interpretation.

PMID:29155098 SUPPORT Human Clinical

"P2, P3 and P4 suffered from AIHA, autoimmune thrombocytopenia, neutropenia and antiphospholipid syndrome"

The series that reports autoimmunity most frequently — three of its patients, with named cytopenias.

PMID:26469693 REFUTE Human Clinical

"Lymphoproliferation and autoimmunity are less common in patients with LoF mutations in ORAI1, and autoimmune thrombocytopenia and neutropenia have been observed in only 1 of 7 patients."

Cuts against autoimmunity being a core recurrent feature of ORAI1 deficiency. Graded REFUTE because it contradicts the frequency claim, not the existence of the phenomenon — and note it draws the ORAI1/STIM1 contrast explicitly, which is why it matters for this entry rather than for CRAC channelopathy in general.

+ 2 more references

Impaired Skeletal Muscle Calcium Handling

A congenital, non-progressive muscular hypotonia is part of the core syndrome. Store-operated calcium entry contributes to refilling sarcoplasmic reticulum calcium stores in skeletal muscle, and its loss produces a myopathy that is present from birth and does not progress in the way an inflammatory or dystrophic myopathy would.

skeletal muscle fiber CL:0008002

sarcoplasmic reticulum calcium refilling GO:0070296 ↓ DECREASED skeletal muscle contraction GO:0003009 ↓ DECREASED

Downstream

Congenital Muscular Hypotonia The clinical expression of the muscle arm, present from birth and non-progressive.

Show evidence (1 reference)

PMID:20004786 SUPPORT Human Clinical

"congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification"

Names congenital myopathy as a component of the ORAI1 deficiency syndrome.

Defective Enamel Mineralization

Ameloblasts depend on CRAC-mediated calcium influx to supply the calcium used to mineralize enamel. Loss of that supply produces an amelogenesis imperfecta-like enamel phenotype affecting both deciduous and permanent teeth, with discoloration, hypoplasia, increased wear and chipping. In some reported patients the dental problem was the chief presenting complaint.

ameloblast CL:0000059

enamel mineralization GO:0070166 ↓ DECREASED

Downstream

Amelogenesis Imperfecta The clinical enamel phenotype, affecting deciduous and permanent dentition.

Show evidence (2 references)

PMID:30114531 SUPPORT Human Clinical

"Enamel mineralization relies on Ca2+ availability provided by Ca2+ release activated Ca2+ (CRAC) channels."

States the dependence of enamel mineralization on CRAC channel calcium supply, which is the mechanism of this node.

PMID:30114531 SUPPORT Human Clinical

"The reported enamel defects are apparent in both the deciduous and in permanent teeth and often require extensive dental treatment to provide the patient with a functional dentition."

Documents the clinical extent of the enamel phenotype in CRAC channelopathy patients.

Sweat Gland Secretory Failure

Anhidrosis or hypohidrosis, part of the ectodermal dysplasia component of the syndrome. Sweat gland fluid secretion is calcium-dependent, and loss of store-operated calcium entry in sweat gland secretory cells is the presumed mechanism. The step from SOCE loss to failed secretion has been reasoned from the phenotype rather than measured directly in patient sweat gland tissue, which is why the incoming edge is marked indirect.

Downstream

Anhidrosis Absent or markedly reduced sweating, with the attendant risk of hyperthermia.

Show evidence (1 reference)

PMID:30114531 SUPPORT Human Clinical

"ectodermal dysplasia with defects in sweat gland function and abnormal enamel mineralization similar to amelogenesis imperfecta (AI)"

Names sweat gland functional failure as a component of CRAC channelopathy.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

6

Blood 2

Autoimmune Hemolytic Anemia HP:0001890

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"P2, P3 and P4 suffered from AIHA, autoimmune thrombocytopenia, neutropenia and antiphospholipid syndrome"

Names autoimmune haemolytic anaemia specifically, in three patients of this series, which is what this phenotype's HP term asserts.

Hemophagocytic Lymphohistiocytosis Hemophagocytosis HP:0012156

Show evidence (1 reference)

PMID:28633876 SUPPORT Human Clinical

"Here, we report the first case of HLH in a patient with a severe defect in lymphocyte activation due to a novel mutation in ORAI1, providing further evidence for an additional pathway of pathogenesis of the HLH syndrome, independent of T- and NK-cell activation."

Documents HLH as a presenting manifestation of ORAI1 deficiency and the authors' interpretation of why it is mechanistically unexpected.

Head and Neck 1

Amelogenesis Imperfecta HP:0000705

Show evidence (1 reference)

PMID:30114531 SUPPORT Human Clinical

"Among the dental phenotypes observed in the patients, discoloration, increased wear, hypoplasias (thinning of enamel) and chipping has been reported."

Enumerates the enamel abnormalities seen in CRAC channelopathy patients.

Immune 1

Combined Immunodeficiency HP:0005387

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms."

Names combined immunodeficiency as the immunological phenotype.

Integument 1

Anhidrosis HP:0000970

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency"

States anhidrosis directly as a feature of ORAI1-deficient patients.

Musculoskeletal 1

Congenital Muscular Hypotonia Generalized hypotonia HP:0001290

Course: STABLE

Show evidence (1 reference)

PMID:20111871 SUPPORT Human Clinical

"immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia"

Names congenital myopathy as one of the three defining clinical components of CRAC channelopathy.

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Genetic Associations

1

ORAI1

Gene: ORAI1 hgnc:25896 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:16582901 SUPPORT Human Clinical

"Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments."

The gene-discovery result establishing ORAI1 as the disease gene.

PMID:26469693 SUPPORT Human Clinical

"By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation"

Establishes that gain-of-function ORAI1 variants cause a distinct, dominantly inherited disease spectrum, which is why this entry is scoped to loss of function only.

💊

Medical Actions

5

Allogeneic Hematopoietic Stem Cell Transplantation

Action: hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

Replacing the haematopoietic compartment restores ORAI1-competent lymphocytes and is the only intervention that addresses the immunodeficiency itself. It is not expected to correct the myopathy, enamel or sweat gland arms, which are intrinsic to non-haematopoietic tissue — a limitation recorded as a knowledge gap rather than asserted, since the published follow-up is too small to have confirmed it.

Mechanism Target:

RESTORES Impaired T Cell Effector Function — Donor-derived lymphocytes carry functional ORAI1 and can mount calcium-dependent effector responses.

Antimicrobial Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Prophylaxis against opportunistic infection and prompt treatment of intercurrent infection, as for other combined immunodeficiencies, pending or in the absence of transplantation.

Mechanism Target:

MODULATES Susceptibility to Severe Infection — Reduces infectious burden without addressing the underlying signalling defect.

Dental Restoration

Action: dental restorative treatment Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Extensive restorative dental treatment is often required to give these patients a functional dentition, given the severity of the enamel defect.

Mechanism Target:

MODULATES Defective Enamel Mineralization — Restores dental function without addressing the mineralization defect itself.

Show evidence (1 reference)

PMID:30114531 SUPPORT Human Clinical

"often require extensive dental treatment to provide the patient with a functional dentition"

States the need for extensive restorative dental treatment in these patients.

Immunoglobulin Replacement

Action: Supportive Care NCIT:C15747

Platform: Protein replacement

Immunoglobulin replacement for antibody insufficiency, as in other combined immunodeficiencies. Recorded as standard combined-immunodeficiency management rather than as an ORAI1-specific intervention: no study has reported its use or effect in ORAI1-deficient patients specifically, and this entry does not imply one has.

Mechanism Target:

MODULATES Susceptibility to Severe Infection — Passive antibody cover. It does not restore store-operated calcium entry or the cellular arm of the defect.

Heat Avoidance and Cooling

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Avoidance of heat stress and active cooling strategies. A specific and easily overlooked requirement in these patients: they cannot sweat, so hyperthermia is a real hazard independent of the immunodeficiency, and it is not corrected by transplantation.

Mechanism Target:

MODULATES Sweat Gland Secretory Failure — Compensates behaviourally for absent evaporative cooling. It does not restore sweat gland function.

🔬

Diagnosis

2

Store-operated calcium entry measurement

Functional demonstration of absent store-operated calcium entry in patient lymphocytes or fibroblasts, typically by calcium imaging after store depletion. This is the assay that defines the CRAC channelopathies as a group and was how the founding kindred was characterised before the gene was known.

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry"

Lists SOCE measurement alongside expression and flow analysis as the diagnostic workup applied to these patients.

ORAI1 sequencing

Molecular confirmation by sequencing ORAI1. In a patient with combined immunodeficiency plus anhidrosis and enamel defects, ORAI1 and STIM1 are the two genes to sequence together, since they produce a nearly superimposable syndrome.

Show evidence (1 reference)

PMID:20004786 SUPPORT Human Clinical

"DNA sequence analysis for mutations in the genes ORAI1, ORAI2, ORAI3, and stromal interaction molecule (STIM) 1 and 2"

Describes the sequencing panel used to establish the diagnosis in these patients.

📊

Prevalence

1

Worldwide, published cases

Cases In Literature Ultra Rare

Only a handful of kindreds have been published since the gene was identified in 2006. No incidence or prevalence estimate exists, and none is computable from a cohort of this size.

Show evidence (1 reference)

PMID:29155098 SUPPORT Human Clinical

"We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein..."

The study describes four patients from three unrelated kindreds with recessive ORAI1 mutations, combined immunodeficiency and abolished ORAI1 expression/SOCE. These are study case counts, not a complete worldwide census or a population rate.

🐁

Animal Models

1

Orai1 knockout mouse

Constitutive Orai1 null mouse. Used here for the store-operated calcium entry lesion itself; note that the reported reproductive phenotype has no human counterpart, because ORAI1-null patients rarely survive to reproductive age.

Species

Mouse

Genotype

Orai1-/-

Publication

PMID:26969191

Pathograph links

Abolished Store-Operated Calcium Entry partially recapitulates fidelity: moderate The mouse reproduces the underlying loss of ORAI1-dependent store-operated calcium entry, which is the shared upstream lesion.

Limitations: The phenotype emphasised in this model is male infertility with defective spermatogenesis, which is not a described feature of the human disease — human ORAI1-null patients rarely reach reproductive age, so the human counterpart is unobservable rather than absent. The model therefore speaks to the cellular lesion, not to the human clinical syndrome.

Show evidence (2 references)

PMID:26969191 SUPPORT Model Organism

"We reveal that Orai1(-/-) male mice are sterile and have severe defects in spermatogenesis, with prominent deficiencies in mid- to late-stage elongating spermatid development."

Documents the murine phenotype, which is the basis for treating this model as only partially recapitulating the human disease.

+ 1 more reference

{ }

Source YAML

click to show

name: ORAI1 Deficiency
creation_date: "2026-08-31T21:30:00Z"
category: Mendelian
synonyms:
- combined immunodeficiency due to ORAI1 deficiency
- CRAC channelopathy due to ORAI1 deficiency
- immunodeficiency 9
- IMD9
- ORAI1 CRAC channelopathy
disease_term:
  preferred_term: combined immunodeficiency due to ORAI1 deficiency
  term:
    id: MONDO:0013007
    label: combined immunodeficiency due to ORAI1 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 —
      congenital myopathy and anhidrotic ectodermal dysplasia with enamel
      defects — which is the defining shape of the IUIS syndromic-CID group,
      and the same placement the KB gives IKBKG-related anhidrotic ectodermal
      dysplasia with immunodeficiency. Note this cuts against the MONDO
      placement of the sibling `immunodeficiency 9` concept under severe
      combined immunodeficiency: lymphocyte development is normal here and
      the defect appears on stimulation.
    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: "ORAI-1 deficiency ORAI1 AR 610277 Normal, defective TCR mediated activation"
      explanation: >
        The ORAI-1 deficiency row of the IUIS table, naming the gene, the
        autosomal recessive inheritance, and normal T cell numbers with
        defective TCR-mediated activation — the function-not-development
        distinction this entry is built around. That 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 own placement rather than an inference
        from the phenotype. Graded OTHER because the source is an
        expert-committee classification document, not a study.
description: >
  ORAI1 deficiency is an autosomal recessive CRAC (calcium release-activated
  calcium) channelopathy. ORAI1 is the pore-forming subunit of the plasma
  membrane CRAC channel; when endoplasmic reticulum calcium stores are
  depleted, the ER calcium sensor STIM1 gates ORAI1 to produce sustained
  store-operated calcium entry (SOCE). Biallelic loss-of-function ORAI1
  variants abolish SOCE, and the resulting failure of calcium/calcineurin/NFAT
  signalling produces a combined immunodeficiency in which lymphocyte
  *development* is essentially normal but lymphocyte *function* is not: T cells
  are present in normal numbers yet fail to produce cytokines on stimulation.
  The clinical syndrome is a triad of combined immunodeficiency with
  life-threatening infection in infancy, a congenital non-progressive muscular
  hypotonia, and anhidrotic ectodermal dysplasia with defective dental enamel
  mineralization. Autoimmunity — most often autoimmune haemolytic anaemia or
  thrombocytopenia — is reported as a fourth feature and tracks with markedly
  reduced invariant natural killer T and regulatory T cell numbers, but how
  commonly it occurs in ORAI1 deficiency specifically is disputed: the series
  published up to 2015 record the same single autoimmune patient — one of six
  in the 2009 case series, one of seven in the 2015 review once a later
  patient is included — while Lian 2018 reports three affected patients. Both
  readings are recorded below rather than one being chosen. Despite
  near-ubiquitous ORAI1 expression across tissues, the phenotype is confined
  to these few organ systems, implying that CRAC-mediated calcium entry is
  non-redundant in only a small number of cell types. The disease is
  ultra-rare, with the published literature amounting to a handful of
  kindreds. Allogeneic haematopoietic stem cell transplantation addresses the
  immunological arm; it is not expected to correct the myopathic or ectodermal
  arms, which are cell-intrinsic to non-haematopoietic tissue, though the
  published follow-up is too short to have confirmed that.
notes: >
  Ultra-rare. The published cohort is a small number of kindreds: the founding
  SCID family with the homozygous ORAI1 p.R91W missense allele (Feske et al.,
  Nature 2006), two further unrelated families with a frameshift and a
  compound heterozygous missense genotype (McCarl et al., JACI 2009), and
  three further unrelated kindreds homozygous for p.V181SfsX8, p.L194P and
  p.G98R (Lian et al., JACI 2018). Counts in this entry are therefore counts
  of kindreds or patients, never frequencies, and `frequency` is deliberately
  left unset throughout rather than computed from a cohort this small.

  The entry is deliberately careful about one distinction that the disease
  name invites people to get wrong. This is a combined immunodeficiency of
  lymphocyte *function*, not of lymphocyte *development*: patients have normal
  or near-normal T, B and NK cell counts and normal thymic output, and the
  defect appears on stimulation. That is what separates ORAI1 deficiency from
  the classical T-B-NK- severe combined immunodeficiencies it is often
  grouped with, and it is why the pathograph routes through cytokine
  transcription rather than through a lymphopoiesis node.

  The sibling disease STIM1 deficiency (MONDO:0013008, curated as
  `kb/disorders/STIM1_Deficiency.yaml`) produces a closely
  overlapping syndrome through loss of the ER calcium sensor that gates ORAI1,
  and both sit under `combined immunodeficiency due to CRAC channel
  dysfunction` (MONDO:0015695). The 2015 review calls the two phenotypes
  "almost identical" and names autoimmune cytopenias as the one apparent
  difference, being commoner in STIM1 deficiency — while cautioning that the
  small patient numbers and early mortality may be what produces that
  difference. The Autoimmunity node below carries that dispute.

  No `has_subtypes` relationship is asserted between them here: they are
  separate genes and separate MONDO concepts, and the right structure for the
  pair is a future grouping, not a subtype list.

  Anhidrotic ectodermal dysplasia with immunodeficiency (AED-ID) is also
  caused by defects in NF-kappaB signalling (IKBKG/NEMO, NFKBIA). The
  ORAI1-associated form is a phenotypic convergence on a different mechanism,
  not a variant of those, and Lian et al. make that point explicitly. It is
  recorded in `discussions` rather than left implicit, because the overlap is
  a real differential-diagnosis trap.

  **ORAI1 is a two-faced gene, and this entry is only one of its faces.**
  Autosomal *dominant* gain-of-function ORAI1 variants constitutively activate
  the CRAC channel and cause an entirely different, overlapping spectrum that
  includes tubular aggregate myopathy and Stormorken syndrome. Those are not
  "ORAI1 deficiency" and are not curated here. The distinction matters
  practically: a literature search on ORAI1 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.

  **`channelopathy_category` is deliberately unset.**
  `ChannelopathyOrganSystemEnum` offers cardiac, skeletal muscle,
  neurological and epithelial, and none of them names an immune
  channelopathy — which is what this disease principally is. Recording that
  here so a future curator does not force one of the four onto it; the
  enum needs an immune value, not this entry needs a wrong one.

  No `conforms_to` was declared. The candidate module families were 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 STIM1
  deficiency are its first two conformers.

  **Deep-research provenance.** An OpenScientist run
  (`research/ORAI1_Deficiency-deep-research-openscientist.md`) is committed
  alongside this entry; `just preflight-dr` scores it PASS with ORAI1 at 59
  mentions and a matching OMIM (612782), and 13/13 of its references resolved
  with 11/13 on topic. It contributed the haemophagocytic lymphohistiocytosis
  presentation (PMID:28633876) and the gain-of-function contrast
  (PMID:26469693) recorded above. Every quote used 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 or compound heterozygous for
    loss-of-function ORAI1 alleles. Heterozygous carriers are clinically
    unaffected, although their T cells show measurably impaired store-operated
    calcium entry, indicating a gene-dosage effect at the cellular level that
    does not reach a clinical threshold.
  evidence:
  - reference: PMID:16582901
    reference_title: "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The SCID patients are homozygous for a single missense mutation in ORAI1"
    explanation: >
      Establishes homozygosity for a single ORAI1 allele in the founding
      kindred, i.e. autosomal recessive inheritance.
  - reference: PMID:19075015
    reference_title: "The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: >
      Documents that carriers are clinically unaffected while showing a
      partial cellular phenotype, which is the basis for the recessive
      classification.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Only a handful of kindreds have been published since the gene was
    identified in 2006. No incidence or prevalence estimate exists, and none
    is computable from a cohort of this size.
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID,
      autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were
      homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed
      ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. ... We here
      identify 4 patients from unrelated kindreds with 3 novel autosomal recessive mutations in
      ORAI1. All mutations resulted in abolished ORAI1 protein expression and SOCE.
    explanation: >-
      The study describes four patients from three unrelated kindreds with recessive ORAI1
      mutations, combined immunodeficiency and abolished ORAI1 expression/SOCE. These are study case
      counts, not a complete worldwide census or a population rate.
pathophysiology:
- name: Biallelic Loss-of-Function ORAI1 Variants
  biological_scale: MOLECULAR
  description: >
    Homozygous or compound heterozygous ORAI1 variants. Reported alleles
    include the founding p.R91W missense change, frameshift/nonsense alleles
    (p.A88SfsX25, p.V181SfsX8), and missense alleles p.A103E, p.L194P and
    p.G98R. Frameshift and several missense alleles abolish ORAI1 protein
    expression outright; p.R91W leaves protein expressed but non-conducting,
    so both null and functionally-null genotypes converge on the same cellular
    phenotype.
  genes:
  - preferred_term: ORAI1
    term:
      id: hgnc:25896
      label: ORAI1
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    description: >-
      Germline biallelic ORAI1 alleles. Both protein-abolishing (frameshift,
      nonsense, several missense) and expression-preserving but
      pore-inactivating (p.R91W) mechanisms are represented.
    allelic_events:
    - MISSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:20004786
    reference_title: "ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient is homozygous for a frameshift nonsense mutation in ORAI1 (ORAI1-A88SfsX25), and a second patient is compound heterozygous for 2 missense mutations in ORAI1 (ORAI1-A103E/L194P). All 3 mutations abolish ORAI1 expression and impair Ca2+ influx and CRAC channel function."
    explanation: >
      Documents the allelic spectrum and that the variants abolish ORAI1
      expression, establishing loss of function as the disease mechanism.
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts."
    explanation: >
      Extends the allelic spectrum and confirms that the variants suppress
      ORAI1 protein and store-operated calcium entry in patient cells.
  downstream:
  - target: Loss of CRAC Channel Pore Function
    description: >-
      Absent or non-conducting ORAI1 protein cannot form a functional CRAC
      channel pore in the plasma membrane.
    causal_link_type: DIRECT

- name: Loss of CRAC Channel Pore Function
  biological_scale: MOLECULAR
  description: >
    ORAI1 is the pore-forming subunit of the CRAC channel. Without functional
    ORAI1, STIM1 has no pore to gate on store depletion, and the CRAC current
    (I_CRAC) is absent. That ORAI1 is the pore rather than a regulator is
    established by the rescue experiment: expressing wild-type Orai1 in
    patient SCID T cells restores both store-operated calcium influx and
    I_CRAC.
  molecular_functions:
  - preferred_term: store-operated calcium channel activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0015279
      label: store-operated calcium channel activity
  evidence:
  - reference: PMID:16582901
    reference_title: "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC))"
    explanation: >
      The rescue result establishes that loss of ORAI1 is what removes CRAC
      channel function, rather than a correlated defect.
  downstream:
  - target: Abolished Store-Operated Calcium Entry
    description: >-
      With no conducting CRAC pore, 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. Its loss is demonstrable in patient T cells,
    fibroblasts and other cell types, and is the single cellular lesion from
    which every downstream arm of the disease follows. Because ORAI1 is
    expressed almost ubiquitously, 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 ORAI1 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: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:20004786
    reference_title: "ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast with the limited clinical phenotype, we found ORAI1 protein expression in a wide variety of cell types and organs."
    explanation: >
      Establishes the expression/phenotype mismatch that makes SOCE
      non-redundancy, rather than expression pattern, the explanation for
      which organs are affected.
  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 Skeletal Muscle Calcium Handling
    description: >-
      Loss of SOCE in skeletal muscle fibres, where it contributes to
      refilling of sarcoplasmic reticulum calcium stores.
    causal_link_type: DIRECT
  - target: Defective Enamel Mineralization
    description: >-
      Ameloblasts depend on CRAC-mediated calcium influx to supply the
      calcium used for enamel mineralization.
    causal_link_type: DIRECT
  - target: Hemophagocytic Lymphohistiocytosis
    description: >-
      HLH has been reported as a presenting manifestation. The route is
      deliberately left unspecified: HLH is normally understood as a
      T-cell-driven syndrome, and these patients have a severe defect in
      lymphocyte activation, so the reporting authors proposed a pathway
      independent of T- and NK-cell activation rather than a mechanism through
      the nodes above.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - A T- and NK-cell-activation-independent route to HLH was proposed but not identified
  - target: Sweat Gland Secretory Failure
    description: >-
      Loss of SOCE in sweat gland secretory cells, whose fluid secretion is
      calcium-dependent.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Calcium-dependent secretory signalling in eccrine sweat gland secretory cells

- 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 large
    NFAT-dependent transcriptional programme — cytokines, chemokines and many
    other genes required for a productive immune response — 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:17572487
    reference_title: "Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the underlying defect in a family with a hereditary severe combined immune deficiency (SCID) syndrome is a defect in CRAC channel function, store-operated Ca(2+) entry, NFAT activation and transcription of cytokines, chemokines and many other NFAT target genes whose transcription is essential for productive immune defence"
    explanation: >
      States the full causal chain from CRAC channel failure through NFAT to
      the transcriptional defect, in the patients themselves.
  downstream:
  - target: Impaired T Cell Effector Function
    description: >-
      Cytokine genes are NFAT targets; their transcription fails.
    causal_link_type: DIRECT
  - target: Reduced Invariant NKT and Regulatory T Cell Numbers
    description: >-
      Development of iNKT and regulatory T cell lineages is
      calcium/NFAT-dependent, unlike conventional T cell development.
    causal_link_type: DIRECT

- name: Impaired T Cell Effector Function
  biological_scale: CELLULAR
  description: >
    The defining immunological abnormality. T cells are present in normal
    numbers and develop normally, but fail to produce cytokines and fail to
    proliferate on stimulation. This is a functional, not a developmental,
    combined immunodeficiency — the point at which ORAI1 deficiency separates
    from the classical T-negative severe combined immunodeficiencies.
  biological_processes:
  - preferred_term: cytokine production by T cells
    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:20004786
    reference_title: "ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical syndrome associated with ORAI1 deficiency is characterized by immunodeficiency with a defect in the function but not in the development of lymphocytes"
    explanation: >
      States the function-versus-development distinction that defines this
      node and distinguishes the disease from developmental SCIDs.
  downstream:
  - target: Susceptibility to Severe Infection
    description: >-
      Loss of T cell effector output leaves the patient unable to control
      viral, bacterial and fungal pathogens.
    causal_link_type: DIRECT

- name: Reduced Invariant NKT and Regulatory T Cell Numbers
  biological_scale: CELLULAR
  description: >
    Beyond the functional defect in conventional T cells, ORAI1-deficient
    patients have strongly reduced numbers of invariant natural killer T cells
    and regulatory T cells, and altered composition of gamma-delta T cell and
    NK cell subsets. Loss of the regulatory compartment is the most plausible
    route from a calcium-signalling defect to the autoimmunity these patients
    develop, which is otherwise a counterintuitive feature of an
    immunodeficiency.
  cell_types:
  - preferred_term: regulatory T cell
    term:
      id: CL:0000815
      label: regulatory T cell
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulatory T cell differentiation
    modifier: DECREASED
    term:
      id: GO:0045066
      label: regulatory T cell differentiation
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets."
    explanation: >
      Directly documents the reduced iNKT and Treg compartments in patients.
  downstream:
  - target: Autoimmunity
    description: >-
      Depletion of the regulatory T cell compartment removes peripheral
      tolerance restraint.
    causal_link_type: DIRECT

- name: Susceptibility to Severe Infection
  biological_scale: ORGANISM
  description: >
    Recurrent and life-threatening infection presenting in infancy, the
    clinical presentation that brings these patients to attention. Untreated,
    the immunodeficiency is fatal in early childhood.
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms."
    explanation: >
      Establishes combined immunodeficiency, with accompanying autoimmunity
      and extra-immune features, as the clinical syndrome.
  downstream:
  - target: Combined Immunodeficiency
    description: >-
      The clinical immunodeficiency phenotype, presenting in infancy with
      severe infection.
    causal_link_type: DIRECT

- name: Autoimmunity
  biological_scale: ORGANISM
  description: >
    Autoimmune cytopenias — haemolytic anaemia and thrombocytopenia — occur in
    ORAI1-deficient patients alongside the immunodeficiency, and where they
    occur they are attributed to loss of the regulatory T cell compartment
    rather than to the effector defect. How often they occur is disputed and
    the entry does not settle it. The published series up to 2015 record the
    same single autoimmune patient — 1 of 6 in the 2009 report, which states
    it covers every ORAI1 patient then known, and 1 of 7 in the 2015 review,
    whose denominator is those six plus one later patient — and the review
    calls autoimmunity less common in ORAI1 than in STIM1 deficiency on that
    basis. Lian 2018 then reported three affected patients in one series. So
    the disagreement is between an early near-complete census and a later
    series, not between two independent cohorts. The review itself notes that
    the small patient numbers and early mortality may censor the observation
    rather than establish a low rate. The node is retained because the
    phenomenon is real and mechanistically informative about the Treg
    compartment, not because it is a recurrent feature of every patient.
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity."
    explanation: >
      Links the reduced regulatory compartment to the autoimmune phenotype,
      as the authors' own interpretation.
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P2, P3 and P4 suffered from AIHA, autoimmune thrombocytopenia, neutropenia and antiphospholipid syndrome"
    explanation: >
      The series that reports autoimmunity most frequently — three of its
      patients, with named cytopenias.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphoproliferation and autoimmunity are less common in patients with LoF mutations in ORAI1, and autoimmune thrombocytopenia and neutropenia have been observed in only 1 of 7 patients."
    explanation: >
      Cuts against autoimmunity being a core recurrent feature of ORAI1
      deficiency. Graded REFUTE because it contradicts the frequency claim,
      not the existence of the phenomenon — and note it draws the ORAI1/STIM1
      contrast explicitly, which is why it matters for this entry rather than
      for CRAC channelopathy in general.
  - reference: PMID:20004786
    reference_title: "ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmunity was observed in only one (P4) out of six ORAI1 deficient patients who presented with neutropenia and thrombocytopenia."
    explanation: >
      The earlier near-complete census the review's 1-of-7 tally builds on,
      not a separate cohort — this report states its six patients are every
      ORAI1 patient then known, and its P4 is the same individual the review
      counts. Kept as its own item because it names the patient and the
      cytopenias, which the review's summary sentence does not.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    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 hedging its own low estimate: the observed rate may reflect
      patients dying or being transplanted before autoimmunity can appear,
      rather than a genuinely lower rate. Graded SUPPORT because it argues
      the phenomenon may be under-observed rather than absent, which is the
      reading this node takes.
  downstream:
  - target: Autoimmune Hemolytic Anemia
    description: >-
      Autoimmune destruction of erythrocytes, one of the autoimmune
      cytopenias reported in CRAC channelopathy.
    causal_link_type: DIRECT

- name: Impaired Skeletal Muscle Calcium Handling
  biological_scale: TISSUE
  description: >
    A congenital, non-progressive muscular hypotonia is part of the core
    syndrome. Store-operated calcium entry contributes to refilling
    sarcoplasmic reticulum calcium stores in skeletal muscle, and its loss
    produces a myopathy that is present from birth and does not progress in
    the way an inflammatory or dystrophic myopathy would.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: sarcoplasmic reticulum calcium refilling
    modifier: DECREASED
    term:
      id: GO:0070296
      label: sarcoplasmic reticulum calcium ion transport
  - preferred_term: skeletal muscle contraction
    modifier: DECREASED
    term:
      id: GO:0003009
      label: skeletal muscle contraction
  evidence:
  - reference: PMID:20004786
    reference_title: "ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "congenital myopathy, and anhydrotic ectodermal dysplasia with a defect in dental enamel calcification"
    explanation: >
      Names congenital myopathy as a component of the ORAI1 deficiency
      syndrome.
  downstream:
  - target: Congenital Muscular Hypotonia
    description: The clinical expression of the muscle arm, present from birth and non-progressive.
    causal_link_type: DIRECT

- name: Defective Enamel Mineralization
  biological_scale: TISSUE
  description: >
    Ameloblasts depend on CRAC-mediated calcium influx to supply the calcium
    used to mineralize enamel. Loss of that supply produces an amelogenesis
    imperfecta-like enamel phenotype affecting both deciduous and permanent
    teeth, with discoloration, hypoplasia, increased wear and chipping. In
    some reported patients the dental problem was the chief presenting
    complaint.
  cell_types:
  - preferred_term: ameloblast
    term:
      id: CL:0000059
      label: ameloblast
  biological_processes:
  - preferred_term: enamel mineralization
    modifier: DECREASED
    term:
      id: GO:0070166
      label: enamel mineralization
  evidence:
  - reference: PMID:30114531
    reference_title: "CRAC channels in dental enamel cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Enamel mineralization relies on Ca2+ availability provided by Ca2+ release activated Ca2+ (CRAC) channels."
    explanation: >
      States the dependence of enamel mineralization on CRAC channel calcium
      supply, which is the mechanism of this node.
  - reference: PMID:30114531
    reference_title: "CRAC channels in dental enamel cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The reported enamel defects are apparent in both the deciduous and in permanent teeth and often require extensive dental treatment to provide the patient with a functional dentition."
    explanation: >
      Documents the clinical extent of the enamel phenotype in CRAC
      channelopathy patients.
  downstream:
  - target: Amelogenesis Imperfecta
    description: >-
      The clinical enamel phenotype, affecting deciduous and permanent
      dentition.
    causal_link_type: DIRECT

- name: Sweat Gland Secretory Failure
  biological_scale: TISSUE
  description: >
    Anhidrosis or hypohidrosis, part of the ectodermal dysplasia component of
    the syndrome. Sweat gland fluid secretion is calcium-dependent, and loss
    of store-operated calcium entry in sweat gland secretory cells is the
    presumed mechanism. The step from SOCE loss to failed secretion has been
    reasoned from the phenotype rather than measured directly in patient sweat
    gland tissue, which is why the incoming edge is marked indirect.
  evidence:
  - reference: PMID:30114531
    reference_title: "CRAC channels in dental enamel cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ectodermal dysplasia with defects in sweat gland function and abnormal enamel mineralization similar to amelogenesis imperfecta (AI)"
    explanation: >
      Names sweat gland functional failure as a component of CRAC
      channelopathy.
  downstream:
  - target: Anhidrosis
    description: >-
      Absent or markedly reduced sweating, with the attendant risk of
      hyperthermia.
    causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: canonical_soce_nfat_failure_model
  hypothesis_label: Canonical SOCE / calcineurin-NFAT Transcriptional Failure Model
  status: CANONICAL
  description: >-
    Biallelic ORAI1 loss removes the CRAC channel pore, abolishing
    store-operated calcium entry; the resulting failure to activate
    calcineurin leaves NFAT cytoplasmic and the NFAT-dependent cytokine
    programme uninduced, which produces a functional rather than
    developmental combined immunodeficiency. The same cellular lesion in
    skeletal muscle, ameloblasts and sweat gland explains the non-immune
    arms. This model is supported by the rescue of both SOCE and I_CRAC by
    wild-type ORAI1 in patient T cells.
discussions:
- discussion_id: orai1_expression_phenotype_mismatch
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is the clinical phenotype restricted to lymphocytes, skeletal muscle,
    ameloblasts and sweat glands when ORAI1 protein is expressed in a wide
    variety of cell types and organs?
  attaches_to:
  - pathophysiology#Abolished Store-Operated Calcium Entry
  rationale: >-
    Immunohistochemistry in healthy donors shows broad ORAI1 expression, yet
    the clinical syndrome spares nearly all of those tissues. Either other
    ORAI paralogues or non-CRAC calcium entry routes compensate outside the
    affected tissues, or SOCE is simply not rate-limiting there. Which of
    those it is has not been established, and it matters: it determines
    whether a systemic CRAC-modulating therapy would have off-target
    consequences in tissues that look unaffected at baseline.
- discussion_id: orai1_hsct_non_haematopoietic_arms
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does haematopoietic stem cell transplantation, which replaces the
    lymphoid compartment, leave the myopathy and ectodermal dysplasia
    untouched over long-term follow-up?
  attaches_to:
  - pathophysiology#Impaired Skeletal Muscle Calcium Handling
  - pathophysiology#Defective Enamel Mineralization
  rationale: >-
    The myopathic, enamel and sweat gland arms are cell-intrinsic to
    non-haematopoietic tissue, so transplantation should not correct them.
    The published cohort is too small and follow-up too short for that
    expectation to have been confirmed, and it is the fact that determines
    whether transplantation is a cure or only a rescue of the immunological
    arm.
- discussion_id: orai1_autoimmunity_treg_vs_intrinsic
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the autoimmunity in ORAI1 deficiency driven by regulatory T cell loss,
    or by an independent consequence of impaired calcium signalling in B
    cells and myeloid cells?
  attaches_to:
  - pathophysiology#Autoimmunity
  rationale: >-
    Reduced Treg numbers is the proposed explanation and is the authors' own
    interpretation, stated as "likely" rather than demonstrated. No
    experiment has separated the Treg-loss route from a cell-intrinsic
    tolerance defect elsewhere, and the two would call for different
    immunomodulatory strategies after transplantation.
phenotypes:
- name: Combined Immunodeficiency
  category: Immunological
  description: >
    Recurrent, severe and often life-threatening infection beginning in
    infancy, with normal lymphocyte numbers but impaired lymphocyte function.
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms."
    explanation: >
      Names combined immunodeficiency as the immunological phenotype.
- name: Anhidrosis
  category: Dermatological
  description: >
    Absent or markedly reduced sweating, the ectodermal dysplasia component
    of the syndrome. Carries a real risk of hyperthermia.
  phenotype_term:
    preferred_term: Anhidrosis
    term:
      id: HP:0000970
      label: Anhidrosis
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency"
    explanation: >
      States anhidrosis directly as a feature of ORAI1-deficient patients.
- name: Amelogenesis Imperfecta
  category: Dental
  description: >
    Defective enamel mineralization affecting deciduous and permanent
    dentition, with discoloration, hypoplasia, increased wear and chipping.
  phenotype_term:
    preferred_term: Amelogenesis imperfecta
    term:
      id: HP:0000705
      label: Amelogenesis imperfecta
  evidence:
  - reference: PMID:30114531
    reference_title: "CRAC channels in dental enamel cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the dental phenotypes observed in the patients, discoloration, increased wear, hypoplasias (thinning of enamel) and chipping has been reported."
    explanation: >
      Enumerates the enamel abnormalities seen in CRAC channelopathy
      patients.
- name: Congenital Muscular Hypotonia
  category: Neuromuscular
  description: >
    Non-progressive muscular hypotonia present from birth, distinct from
    dystrophic or inflammatory myopathy.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
    clinical_course: STABLE
  evidence:
  - reference: PMID:20111871
    reference_title: "CRAC channelopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "immunodeficiency, congenital myopathy, and anhydrotic ectodermal dysplasia"
    explanation: >
      Names congenital myopathy as one of the three defining clinical
      components of CRAC channelopathy.
- name: Autoimmune Hemolytic Anemia
  category: Hematological
  description: >
    Autoimmune destruction of erythrocytes, one of the autoimmune cytopenias
    reported in CRAC channelopathy.
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P2, P3 and P4 suffered from AIHA, autoimmune thrombocytopenia, neutropenia and antiphospholipid syndrome"
    explanation: >
      Names autoimmune haemolytic anaemia specifically, in three patients of
      this series, which is what this phenotype's HP term asserts.
- name: Hemophagocytic Lymphohistiocytosis
  category: Hematological
  description: >
    HLH has been reported as the presenting manifestation of ORAI1 deficiency.
    It is mechanistically surprising and worth recording as such: HLH is
    normally understood as a T-cell-driven hyperinflammatory syndrome, and
    these patients have a severe defect in lymphocyte activation. The case
    was put forward by its authors as evidence for a pathway to HLH that does
    not depend on T- and NK-cell activation.
  phenotype_term:
    preferred_term: Hemophagocytosis
    term:
      id: HP:0012156
      label: Hemophagocytosis
  evidence:
  - reference: PMID:28633876
    reference_title: "Hemophagocytic lymphohistiocytosis as presenting manifestation of profound combined immunodeficiency due to an ORAI1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the first case of HLH in a patient with a severe defect in lymphocyte activation due to a novel mutation in ORAI1, providing further evidence for an additional pathway of pathogenesis of the HLH syndrome, independent of T- and NK-cell activation."
    explanation: >
      Documents HLH as a presenting manifestation of ORAI1 deficiency and the
      authors' interpretation of why it is mechanistically unexpected.
genetic:
- name: ORAI1
  gene_term:
    preferred_term: ORAI1
    term:
      id: hgnc:25896
      label: ORAI1
  relationship_type: CAUSATIVE
  notes: >
    ORAI1 encodes the pore-forming subunit of the plasma membrane CRAC
    channel. Biallelic loss-of-function variants cause this disease; the gene
    was identified by combining SNP linkage analysis in the founding SCID
    kindred with a Drosophila RNAi screen for regulators of store-operated
    calcium entry and NFAT nuclear import.
  evidence:
  - reference: PMID:16582901
    reference_title: "A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments."
    explanation: >
      The gene-discovery result establishing ORAI1 as the disease gene.
  - reference: PMID:26469693
    reference_title: "Diseases caused by mutations in ORAI1 and STIM1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, autosomal dominant gain-of-function mutations in ORAI1 and STIM1 result in constitutive CRAC channel activation"
    explanation: >
      Establishes that gain-of-function ORAI1 variants cause a distinct,
      dominantly inherited disease spectrum, which is why this entry is
      scoped to loss of function only.
animal_models:
- name: Orai1 knockout mouse
  species: Mouse
  genotype: Orai1-/-
  publication: PMID:26969191
  description: >
    Constitutive Orai1 null mouse. Used here for the store-operated calcium
    entry lesion itself; note that the reported reproductive phenotype has no
    human counterpart, because ORAI1-null patients rarely survive to
    reproductive age.
  modeled_mechanisms:
  - target: Abolished Store-Operated Calcium Entry
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The mouse reproduces the underlying loss of ORAI1-dependent
      store-operated calcium entry, which is the shared upstream lesion.
    limitations: >-
      The phenotype emphasised in this model is male infertility with
      defective spermatogenesis, which is not a described feature of the
      human disease — human ORAI1-null patients rarely reach reproductive
      age, so the human counterpart is unobservable rather than absent. The
      model therefore speaks to the cellular lesion, not to the human
      clinical syndrome.
    evidence:
    - reference: PMID:26969191
      reference_title: "Male infertility in mice lacking the store-operated Ca(2+) channel Orai1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We reveal that Orai1(-/-) male mice are sterile and have severe defects in spermatogenesis, with prominent deficiencies in mid- to late-stage elongating spermatid development."
      explanation: >-
        Documents the murine phenotype, which is the basis for treating this
        model as only partially recapitulating the human disease.
    - reference: PMID:26969191
      reference_title: "Male infertility in mice lacking the store-operated Ca(2+) channel Orai1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "men with loss-of-function or null mutations in ORAI1 rarely survive to reproductive age"
      explanation: >-
        Explains why the murine reproductive phenotype cannot be checked
        against human patients, which is the translational caveat recorded
        in limitations.
diagnosis:
- name: Store-operated calcium entry measurement
  description: >
    Functional demonstration of absent store-operated calcium entry in
    patient lymphocytes or fibroblasts, typically by calcium imaging after
    store depletion. This is the assay that defines the CRAC channelopathies
    as a group and was how the founding kindred was characterised before the
    gene was known.
  evidence:
  - reference: PMID:29155098
    reference_title: "ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry"
    explanation: >
      Lists SOCE measurement alongside expression and flow analysis as the
      diagnostic workup applied to these patients.
- name: ORAI1 sequencing
  description: >
    Molecular confirmation by sequencing ORAI1. In a patient with combined
    immunodeficiency plus anhidrosis and enamel defects, ORAI1 and STIM1 are
    the two genes to sequence together, since they produce a nearly
    superimposable syndrome.
  evidence:
  - reference: PMID:20004786
    reference_title: "ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA sequence analysis for mutations in the genes ORAI1, ORAI2, ORAI3, and stromal interaction molecule (STIM) 1 and 2"
    explanation: >
      Describes the sequencing panel used to establish the diagnosis in these
      patients.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >
    Replacing the haematopoietic compartment restores ORAI1-competent
    lymphocytes and is the only intervention that addresses the
    immunodeficiency itself. It is not expected to correct the myopathy,
    enamel or sweat gland arms, which are intrinsic to non-haematopoietic
    tissue — a limitation recorded as a knowledge gap rather than asserted,
    since the published follow-up is too small to have confirmed it.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Impaired T Cell Effector Function
    treatment_effect: RESTORES
    description: >-
      Donor-derived lymphocytes carry functional ORAI1 and can mount
      calcium-dependent effector responses.
- name: Antimicrobial Prophylaxis
  description: >
    Prophylaxis against opportunistic infection and prompt treatment of
    intercurrent infection, as for other combined immunodeficiencies, pending
    or in the absence of transplantation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Susceptibility to Severe Infection
    treatment_effect: MODULATES
    description: >-
      Reduces infectious burden without addressing the underlying signalling
      defect.
- name: Dental Restoration
  description: >
    Extensive restorative dental treatment is often required to give these
    patients a functional dentition, given the severity of the enamel defect.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: dental restorative treatment
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Defective Enamel Mineralization
    treatment_effect: MODULATES
    description: >-
      Restores dental function without addressing the mineralization defect
      itself.
  evidence:
  - reference: PMID:30114531
    reference_title: "CRAC channels in dental enamel cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "often require extensive dental treatment to provide the patient with a functional dentition"
    explanation: >
      States the need for extensive restorative dental treatment in these
      patients.
- name: Immunoglobulin Replacement
  description: >
    Immunoglobulin replacement for antibody insufficiency, as in other
    combined immunodeficiencies. Recorded as standard combined-immunodeficiency
    management rather than as an ORAI1-specific intervention: no study has
    reported its use or effect in ORAI1-deficient patients specifically, and
    this entry does not imply one has.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Susceptibility to Severe Infection
    treatment_effect: MODULATES
    description: >-
      Passive antibody cover. It does not restore store-operated calcium
      entry or the cellular arm of the defect.
- name: Heat Avoidance and Cooling
  description: >
    Avoidance of heat stress and active cooling strategies. A specific and
    easily overlooked requirement in these patients: they cannot sweat, so
    hyperthermia is a real hazard independent of the immunodeficiency, and it
    is not corrected by transplantation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Sweat Gland Secretory Failure
    treatment_effect: MODULATES
    description: >-
      Compensates behaviourally for absent evaporative cooling. It does not
      restore sweat gland function.

📚

References & Deep Research

Deep Research

1

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 SCID family with the homozygous ORAI1 p.R91W missense allele (Feske et al., Nature 2006), two further unrelated families with a frameshift and a compound heterozygous missense genotype (McCarl et al., JACI 2009), and three further unrelated kindreds homozygous for p.V181SfsX8, p.L194P and p.G98R (Lian et al., JACI 2018). Counts in this entry are therefore counts of kindreds or patients, never frequencies, and `frequency` is deliberately left unset throughout rather than computed from a cohort this small. The entry is deliberately careful about one distinction that the disease name invites people to get wrong. This is a combined immunodeficiency of lymphocyte *function*, not of lymphocyte *development*: patients have normal or near-normal T, B and NK cell counts and normal thymic output, and the defect appears on stimulation. That is what separates ORAI1 deficiency from the classical T-B-NK- severe combined immunodeficiencies it is often grouped with, and it is why the pathograph routes through cytokine transcription rather than through a lymphopoiesis node. The sibling disease STIM1 deficiency (MONDO:0013008, curated as `kb/disorders/STIM1_Deficiency.yaml`) produces a closely overlapping syndrome through loss of the ER calcium sensor that gates ORAI1, and both sit under `combined immunodeficiency due to CRAC channel dysfunction` (MONDO:0015695). The 2015 review calls the two phenotypes "almost identical" and names autoimmune cytopenias as the one apparent difference, being commoner in STIM1 deficiency — while cautioning that the small patient numbers and early mortality may be what produces that difference. The Autoimmunity node below carries that dispute. No `has_subtypes` relationship is asserted between them here: they are separate genes and separate MONDO concepts, and the right structure for the pair is a future grouping, not a subtype list. Anhidrotic ectodermal dysplasia with immunodeficiency (AED-ID) is also caused by defects in NF-kappaB signalling (IKBKG/NEMO, NFKBIA). The ORAI1-associated form is a phenotypic convergence on a different mechanism, not a variant of those, and Lian et al. make that point explicitly. It is recorded in `discussions` rather than left implicit, because the overlap is a real differential-diagnosis trap. **ORAI1 is a two-faced gene, and this entry is only one of its faces.** Autosomal *dominant* gain-of-function ORAI1 variants constitutively activate the CRAC channel and cause an entirely different, overlapping spectrum that includes tubular aggregate myopathy and Stormorken syndrome. Those are not "ORAI1 deficiency" and are not curated here. The distinction matters practically: a literature search on ORAI1 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. **`channelopathy_category` is deliberately unset.** `ChannelopathyOrganSystemEnum` offers cardiac, skeletal muscle, neurological and epithelial, and none of them names an immune channelopathy — which is what this disease principally is. Recording that here so a future curator does not force one of the four onto it; the enum needs an immune value, not this entry needs a wrong one. No `conforms_to` was declared. The candidate module families were 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 STIM1 deficiency are its first two conformers. **Deep-research provenance.** An OpenScientist run (`research/ORAI1_Deficiency-deep-research-openscientist.md`) is committed alongside this entry; `just preflight-dr` scores it PASS with ORAI1 at 59 mentions and a matching OMIM (612782), and 13/13 of its references resolved with 11/13 on topic. It contributed the haemophagocytic lymphohistiocytosis presentation (PMID:28633876) and the gain-of-function contrast (PMID:26469693) recorded above. Every quote used was re-verified against the fetched reference cache rather than taken from the report.

Create: ORAI1 Deficiency (combined immunodeficiency due to CRAC channelopathy) · 2026-08-31T21:58:46Z · View source

De-novo curation of combined immunodeficiency due to ORAI1 deficiency (MONDO:0013007) resolving curation claim #10296, which replaced claim #10291 after autosomal dominant brachyolmia turned out to be already curated. The pathograph runs biallelic ORAI1 loss of function -> loss of CRAC channel pore function -> abolished store-operated calcium entry, then branches into four organ arms: calcineurin/NFAT transcriptional failure (the immune arm), skeletal muscle calcium handling, ameloblast enamel mineralization, and sweat gland secretion. The immune arm is deliberately modelled as a defect of lymphocyte function rather than development - patients have normal T, B and NK counts and the defect appears on stimulation - which is what separates this from the classical T-negative severe combined immunodeficiencies it is usually grouped with. Autoimmunity is routed through reduced invariant NKT and regulatory T cell numbers rather than asserted directly. The sweat gland edge is marked INDIRECT_KNOWN_INTERMEDIATES because the cellular step has not been measured in patient sweat gland tissue. Three knowledge gaps recorded: why the phenotype is restricted when ORAI1 protein is broadly expressed; whether HSCT leaves the myopathic and ectodermal arms untouched on long follow-up; and whether the autoimmunity is Treg-loss-driven or an independent consequence. The Orai1 null mouse is linked as PARTIALLY_RECAPITULATES with the caveat that its reported male-infertility phenotype has no observable human counterpart because ORAI1-null patients rarely reach reproductive age. Deep research: one OpenScientist run, committed; preflight-dr PASS (ORAI1=59 mentions, OMIM 612782 matching), 13/13 references resolved and 11/13 on topic. It contributed the HLH presentation (PMID:28633876) and the ORAI1 gain-of-function contrast with tubular aggregate myopathy and Stormorken syndrome (PMID:26469693), the latter now recorded in notes so a future curator does not merge the two faces of this gene. Two term errors caught in curation: NCIT device-versus-action confusion was avoided by binding clinical actions only, and HP:0012311 was rejected by linkml-term-validator as Increased total monocyte count - the correct hemophagocytosis term is HP:0012156. Validated with just validate (29/29 snippets verified), just validate-terms, check-entity-refs, check-enum-values, check-snippet-length and check-folded-hyphens.

OpenScientist ▸

ORAI1 Deficiency (CRAC Channelopathy) — Disease Characterization Report

openscientist-autonomous 13 citations 2026-08-31T21:53:10.336776

ORAI1 Deficiency (CRAC Channelopathy) — Disease Characterization Report

Autonomous discovery report. Evidence tiers indicated as: [Human clinical], [Model organism], [In vitro], [Computational/inferred]. Primary citations given as PMID.

Summary / Consensus Answer

ORAI1 Deficiency is an ultra-rare, autosomal-recessive primary immunodeficiency caused by loss-of-function mutations in ORAI1, the gene encoding the pore-forming subunit of the plasma-membrane Ca²⁺ release–activated Ca²⁺ (CRAC) channel. Loss of ORAI1 abolishes store-operated Ca²⁺ entry (SOCE), crippling the Ca²⁺/calcineurin/NFAT signaling axis. The disease — part of the broader entity "CRAC channelopathy" (which also includes STIM1 loss-of-function) — presents as a clinical tetrad: (1) a severe-combined-immunodeficiency (SCID)-like combined immunodeficiency with recurrent/severe infections, (2) autoimmunity/lymphoproliferation, (3) non-progressive congenital muscular hypotonia (myopathy), and (4) anhidrotic ectodermal dysplasia with defective sweating and dental enamel defects (amelogenesis imperfecta). Hematopoietic stem cell transplantation (HSCT) can cure the immunological disease but does not correct the non-hematopoietic (sweat gland, dental, muscle) manifestations.

Important nomenclature note: ORAI1 is a "two-faced" gene. Loss-of-function mutations (the subject of this report) cause the recessive immunodeficiency/CRAC channelopathy described here. Gain-of-function mutations in the same gene cause dominant tubular aggregate myopathy (TAM) and Stormorken syndrome — these are distinct diseases and are NOT "ORAI1 deficiency." They are mentioned only for contrast (PMID: 26469693).

1. Disease Information

Overview: A monogenic (Mendelian) inborn error of immunity in which absent CRAC-channel function eliminates SOCE in immune and non-immune cells. Because SOCE is the dominant Ca²⁺-influx pathway in T lymphocytes, sweat glands, and tooth-forming ameloblasts, the disorder is multisystem.
Key identifiers:
OMIM (phenotype): Immunodeficiency 9 (IMD9) #612782 ("combined immunodeficiency with anhidrotic ectodermal dysplasia").
OMIM (gene): ORAI1 #610277.
Orphanet: "CRAC channelopathy" / "Immunodeficiency due to a defect in CRAC channel" (Orphanet groups ORAI1 and STIM1 LOF together).
Mondo: "immunodeficiency 9" / "combined immunodeficiency due to ORAI1 deficiency" (maps to OMIM #612782; a subtype under immunodeficiency-with-ectodermal-dysplasia); umbrella entity "CRAC channelopathy." (Exact MONDO accession should be verified against the current MONDO release; the OMIM #612782 cross-reference is the stable anchor.)
ICD-10: D81.8 / D81.9 (combined immunodeficiencies, other/unspecified). ICD-11: 4A01.1Y (combined immunodeficiencies).
MeSH: ORAI1 Protein (D000071140); Severe Combined Immunodeficiency (D016511) as related.
HGNC: ORAI1 HGNC:25896; UniProt Q96D31; Ensembl ENSG00000276045 / ENSG00000152580.
Synonyms / alternative names: Immunodeficiency 9; CRAC channelopathy (ORAI1-type); Combined immunodeficiency due to ORAI1 deficiency; ORAI1-CID; "Anhidrotic ectodermal dysplasia with immunodeficiency" (a distinct, ORAI1-specific form — noted by PMID: 29155098 as distinct from NEMO/IKBKG-related EDA-ID); SCID-like disease with SOCE defect. Older literature: "CRAC channel deficiency."
Data source type: Information is disease-level and individual-patient (case-report/case-series) derived. Because <20–30 patients are reported worldwide, evidence comes from small kindreds, functional in-vitro studies of patient cells, and mouse models — not from population EHR or registry aggregates.

2. Etiology

Disease Causal Factors

Primary cause = genetic. Biallelic (homozygous or compound heterozygous) loss-of-function variants in ORAI1 that abolish CRAC-channel function and SOCE [Human clinical; PMID: 16582901, 29155098, 26469693].
No environmental, infectious, or toxic cause initiates the disease; environmental agents act only as downstream triggers of complications (opportunistic infections due to the immunodeficiency).

Risk Factors

Genetic: The causal biallelic ORAI1 LOF genotype is necessary and sufficient. Consanguinity is a major risk factor because homozygous null alleles predominate in reported kindreds (recessive rare disease). Family history of an affected sib or of consanguineous union raises risk.
Environmental / demographic: None established as causal. Heat exposure is a hazard (not a cause) because anhidrosis predisposes to hyperthermia/heat intolerance. Sex is not a risk factor (autosomal).

Protective Factors

Genetic: Heterozygous carriers are clinically unaffected (recessive), although their T cells show partially reduced SOCE — a gene-dosage effect — demonstrating that ~50% channel function is protective [In vitro; PMID: 19075015]. Redundant Ca²⁺-entry contributions from paralogs ORAI2/ORAI3 and STIM2 may partially buffer some cell types (basis of variable non-immune expressivity) [Model organism/in vitro; PMID: 28294127].
Environmental: Avoidance of heat, infection prophylaxis, and immune reconstitution are protective interventions (see §12–13), not innate protective factors.

Gene–Environment Interactions

The genetic immunodeficiency sets susceptibility; pathogen exposure determines which infections manifest. Autoimmune flares may be triggered by infection due to loss of regulatory T-cell tolerance. No formal GxE quantitative data exist for this ultra-rare disease.

3. Phenotypes

Frequencies are qualitative (small n). HPO term suggestions included.

Phenotype	Type	Onset	Severity / Course	Frequency	HPO
Recurrent/severe/opportunistic infections (viral, bacterial, fungal; CMV, EBV, Pneumocystis, candidiasis)	Clinical sign	Neonatal–infantile	Severe, life-threatening; often the presenting feature	Nearly all	HP:0002719 (Recurrent infections), HP:0004430 (Severe combined immunodeficiency)
Combined immunodeficiency with normal lymphocyte counts but impaired T-cell function	Lab abnormality	Congenital	Persistent	~All	HP:0005387 (T-cell dysfunction), HP:0002090-adjacent
Autoimmunity: autoimmune hemolytic anemia, autoimmune thrombocytopenia, lymphoproliferation/HLH	Clinical sign/lab	Infancy–childhood	Variable, can be severe (HLH reported as presenting event)	Common	HP:0001973 (Autoimmune thrombocytopenia), HP:0001890 (Autoimmune hemolytic anemia), HP:0002665 (Lymphadenopathy)
Non-progressive congenital muscular hypotonia / myopathy	Physical/sign	Congenital/neonatal	Non-progressive, generally mild-moderate	Most	HP:0008947 (Infantile muscular hypotonia), HP:0003198 (Myopathy)
Anhidrosis / hypohidrosis (defective sweating) → heat intolerance	Physical sign	Congenital	Lifelong, stable	Most	HP:0000970 (Abnormality of the sweat glands), HP:0000966 (Hypohidrosis), HP:0009927 (Anhidrosis)
Amelogenesis imperfecta / dental enamel defects	Physical sign	With tooth eruption (childhood)	Lifelong, stable	Most	HP:0000705 (Amelogenesis imperfecta), HP:0006297 (Hypoplastic enamel)
Ectodermal dysplasia (broader)	Physical	Congenital	Stable	Common	HP:0000968 (Ectodermal dysplasia)
Failure to thrive / growth failure (secondary to infection)	Sign	Infancy	Variable	Common	HP:0001508 (Failure to thrive)
Splenomegaly/hepatomegaly (lymphoproliferation)	Sign	Childhood	Variable	Subset	HP:0001744 (Splenomegaly)

Quality-of-life impact: High burden — recurrent hospitalizations for infection; lifelong infection prophylaxis; heat intolerance restricts activity/climate tolerance; dental restoration needs; muscle weakness affects motor milestones. Without immune reconstitution, early mortality is common. No formal EQ-5D/SF-36 data exist (ultra-rare).
Evidence: PMID: 29155098 (subset deficits, enamel, anhidrosis, muscular dysplasia); PMID: 26469693 (tetrad); PMID: 28633876 (HLH as presenting manifestation of profound CID).

4. Genetic / Molecular Information

Causal gene: ORAI1 (calcium release-activated calcium modulator 1), 12q24.31, HGNC:25896, OMIM gene #610277, UniProt Q96D31. Encodes a 301-aa tetraspanning (4-transmembrane) plasma-membrane protein; six ORAI1 subunits assemble into the hexameric CRAC-channel pore (concatemer functional analysis, PMID: 27806271; Drosophila Orai hexamer structure PDB 4HKR). Key pore/structural residues: E106 (Ca²⁺ selectivity filter, TM1), R91 (TM1); disease missense mutations (R91W, G98R, L194P) map to transmembrane/pore-proximal regions.
Pathogenic variants (all LOF, biallelic; germline):
c.271C>T, p.Arg91Trp (R91W) — first reported, homozygous; misfolds/mis-gates channel, abolishes CRAC current. Identified by combined SNP-array linkage + a Drosophila RNAi screen; WT ORAI1 re-expression rescued SOCE/I_CRAC in patient T cells, proving causality [PMID: 16582901].
p.Val181SerfsX8 (frameshift), p.Leu194Pro (missense), p.Gly98Arg (missense) — homozygous; suppress ORAI1 protein expression and SOCE [PMID: 29155098].
Additional reported nulls include a nonsense/premature-stop allele (A88Sfs-type) abrogating protein.
Variant classes: missense (pore/TM), frameshift, nonsense/premature termination → all functionally loss-of-function (no/absent channel or non-conducting channel).
ACMG classification: reported alleles are Pathogenic/Likely Pathogenic (functional SOCE assays = strong PS3 evidence; recessive segregation; absent SOCE).
Allele frequency: Causal alleles are absent or ultrarare in gnomAD; ORAI1 is relatively tolerant to heterozygous LOF but biallelic LOF is nearly private to consanguineous kindreds.
Somatic vs germline: Germline exclusively.
Functional consequence: Loss of function (recessive). Contrast: gain-of-function ORAI1 (e.g., p.G98S, p.L138F, p.P245L, p.T184M) → constitutive SOCE → TAM/Stormorken (dominant) — different disease [PMID: 26469693].
Modifier genes: Paralogous ORAI2, ORAI3 and ER sensors STIM1, STIM2 contribute to residual/tissue-specific SOCE and likely modify expressivity of non-immune features [PMID: 28294127].
Epigenetic information: No disease-specific methylation/histone signature reported; not implicated.
Chromosomal abnormalities: None — disease is due to point/small variants, not CNVs or aneuploidy.

5. Environmental Information

Environmental factors: None causal. Pathogen exposure is the principal external factor determining infectious complications.
Lifestyle factors: Not applicable to a Mendelian gene defect; heat/exercise exposure matters clinically due to anhidrosis (risk of hyperthermia).
Infectious agents: Not a cause; opportunistic pathogens (CMV, EBV, Pneumocystis jirovecii, candida, other viruses/bacteria/fungi) act as downstream complications of the T-cell defect [PMID: 26469693; 26109647].

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Biallelic LOF mutation in ORAI1 → loss/non-function of the CRAC-channel pore subunit in the plasma membrane. [Human clinical/in vitro; PMID: 16582901, 29155098]
This results in abolished store-operated Ca²⁺ entry (SOCE): after antigen-receptor engagement, PLCγ → IP₃ depletes ER Ca²⁺ → STIM1 oligomerizes and senses depletion → but with no functional ORAI1, STIM1 cannot open a Ca²⁺ channel, so sustained cytosolic Ca²⁺ influx fails. [In vitro; PMID: 17572487]
Loss of the sustained Ca²⁺ signal leads to failure of calcineurin-mediated NFAT dephosphorylation → NFAT stays cytoplasmic → transcription of IL-2 and other cytokine/chemokine genes fails. [In vitro; PMID: 17572487]
In T cells this results in impaired proliferation, cytokine production, and effector differentiation despite normal lymphocyte numbers → SCID-like combined immunodeficiency → recurrent/opportunistic infections. [Human clinical; PMID: 26469693]
Branch (autoimmunity): SOCE loss results in strongly reduced invariant NKT and regulatory T (Treg) cells and altered γδ-T/NK subsets → breakdown of peripheral tolerance → autoimmune cytopenias, lymphoproliferation, HLH. [Human clinical; PMID: 29155098, 28633876]
Branch (ectodermal — sweat glands): In eccrine sweat-gland epithelium, SOCE drives fluid/electrolyte secretion; ORAI1 loss leads to defective sweat secretion → anhidrosis → heat intolerance. [Inferred from tissue expression + phenotype; PMID: 26469693]
Branch (ectodermal — teeth): In ameloblasts/enamel cells, CRAC-channel (ORAI1/2/3 + STIM1/2) SOCE supplies the large Ca²⁺ flux needed for enamel mineralization — demonstrated directly in primary enamel cells (thapsigargin-evoked SOCE blocked by the CRAC inhibitor Synta-66), most abundant at the maturation stage; ORAI1 loss leads to hypomineralized enamel → amelogenesis imperfecta. [Model/in vitro + human; PMID: 26515404, 28732182, 28352661, 30114531, 29155098]
Branch (muscle): SOCE is required for skeletal-muscle Ca²⁺ homeostasis and development; when impaired, muscle is prone to early fatigue and myopathy, so ORAI1 loss leads to a non-progressive congenital myopathy / muscular hypotonia (a tissue-autonomous defect not corrected by HSCT). [Human clinical + model; PMID: 26469693, 33262706]. Note the symmetry: GOF STIM1/ORAI1 → constitutive SOCE → tubular aggregate myopathy (PMID: 31666234) — both excess and deficiency of SOCE injure muscle.

Category detail

Molecular pathways: Store-operated Ca²⁺ entry / CRAC-channel pathway; Ca²⁺–calcineurin–NFAT signaling (Reactome R-HSA-2672351 "Stimuli-sensing / STIM-ORAI"; KEGG "Calcium signaling pathway" hsa04020). Downstream NFAT target-gene transcription.
Cellular processes: T-cell activation, proliferation, cytokine secretion; immune synapse Ca²⁺ signaling; Treg/iNKT development; sweat-gland fluid secretion; ameloblast biomineralization; myocyte Ca²⁺ handling.
Protein dysfunction: Loss of function — misfolded/mis-gated (missense) or absent (frameshift/nonsense) ORAI1 → non-conducting or absent CRAC channel. Not aggregation-related.
Metabolic changes: No primary metabolic defect; secondary effects on Ca²⁺-dependent mitochondrial/energy signaling possible.
Immune system involvement: Central — combined immunodeficiency plus autoimmunity (immunodysregulation), a hallmark "immunodeficiency-with-autoimmunity" pattern.
Tissue damage mechanisms: Infection-driven tissue injury; autoimmune destruction of blood cells; HLH-associated inflammation.
Biochemical abnormality: Ion-channel defect — loss of Ca²⁺-selective CRAC conductance (the defining biochemical lesion).
Molecular profiling: Patient T cells/fibroblasts show absent SOCE on Ca²⁺ imaging and absent/greatly reduced CRAC current (I_CRAC) on patch-clamp; reduced ORAI1 protein by Western/flow [PMID: 29155098]. No large transcriptomic/proteomic/metabolomic disease atlases exist (ultra-rare).
Functional genomics: Orai1 and Stim1/2 conditional-knockout mice recapitulate SOCE loss and immune defects, confirming causality [Model organism; PMID: 26109647].

Suggested ontology terms

GO (BP): GO:0002115 (store-operated calcium entry), GO:0070588 (calcium ion transmembrane transport), GO:0033173 (calcineurin-NFAT signaling cascade), GO:0042110 (T cell activation).
GO (MF): GO:0015279 (store-operated calcium channel activity).
GO (CC): GO:0005886 (plasma membrane), GO:0034704 (calcium channel complex).
CL: CL:0000084 (T cell), CL:0000815 (regulatory T cell), CL:0000921 (NKT cell), CL:0002064 (ameloblast/enamel-forming cell), CL:0000188 (skeletal muscle cell).

7. Anatomical Structures Affected

Organ / system level:
Primary: Immune system (thymus-derived T-cell compartment, lymphoid tissues) — UBERON:0002405 (immune system); integument/skin adnexa — eccrine sweat glands (UBERON:0001820); teeth/enamel organ (UBERON:0001091 tooth; UBERON:0007375 enamel); skeletal muscle (UBERON:0001134).
Secondary: Blood (autoimmune cytopenias, UBERON:0000178); spleen/liver/lymph nodes (lymphoproliferation); lungs/GI (site of recurrent infection).
Body systems: Immune, integumentary, musculoskeletal, hematologic, dental/craniofacial.
Tissue / cell level:
Epithelial: sweat-gland secretory epithelium; ameloblasts (enamel epithelium).
Immune: T lymphocytes (esp. Treg, iNKT, γδ-T), NK cells.
Muscle: skeletal myofibers.
Cell Ontology: CL:0000084, CL:0000815, CL:0000921, CL:0002064, CL:0000188, CL:0000623 (NK cell).
Subcellular level: Plasma membrane (site of the ORAI1/CRAC channel) and endoplasmic/sarcoplasmic reticulum (STIM1 sensor). GO-CC: GO:0005886 (plasma membrane), GO:0005783 (endoplasmic reticulum), GO:0034704 (calcium channel complex).
Localization / lateralization: Systemic and bilateral/symmetric (generalized anhidrosis, generalized enamel involvement, generalized hypotonia); not focal or lateralized.

8. Temporal Development

Onset: Congenital / neonatal–infantile. Immunodeficiency typically presents in the first months of life with severe infection; muscular hypotonia and anhidrosis are congenital; enamel defects become apparent as teeth erupt (childhood). Onset pattern: early, chronic, with acute infectious/autoimmune exacerbations.
Progression:
Immunodeficiency: persistent/lifelong unless corrected by HSCT; punctuated by acute infections and autoimmune flares (HLH can be fulminant, PMID: 28633876).
Muscular hypotonia: non-progressive (static).
Anhidrosis & enamel defects: stable/lifelong, non-progressive.
Course pattern: Chronic lifelong disease with episodic infectious/autoimmune crises superimposed.
Remission: No spontaneous remission of the underlying channel defect. Treatment-induced immune remission follows successful HSCT (immune compartment), but ectodermal/muscle features persist because they are non-hematopoietic.
Critical period: Infancy is the window of highest mortality and the optimal window for definitive immune therapy (early HSCT before severe infection/organ damage).

9. Inheritance and Population

Epidemiology: Ultra-rare. Fewer than ~30 patients with CRAC channelopathy (ORAI1 + STIM1 LOF combined) reported worldwide; ORAI1-LOF kindreds number a handful. Prevalence/incidence too low to estimate reliably (Orphanet: prevalence <1/1,000,000). No SEER/registry rates.
Inheritance: Autosomal recessive (biallelic LOF). [PMID: 16582901, 29155098]
Penetrance: Complete for the biallelic null genotype (all reported homozygotes affected); heterozygotes unaffected clinically though with subclinical partial SOCE reduction (gene-dosage) [PMID: 19075015].
Expressivity: Variable across the tetrad — infection/immune severity and degree of muscle/ectodermal involvement differ between kindreds (possible paralog modifiers).
Genetic anticipation: Not applicable (not a repeat-expansion disorder).
Germline mosaicism: Not reported.
Founder effects: Individual kindreds carry private homozygous alleles, typically in consanguineous families; no broad founder allele established.
Consanguinity: Major — most reported cases arise from consanguineous unions (hallmark of rare recessive disease).
Carrier frequency: Not established; biallelic pathogenic genotype essentially absent from population databases.
Population demographics: Reported in multiple ethnicities (consanguineous kindreds from various regions); no strong ethnic predilection beyond consanguinity. Sex ratio ~1:1 (autosomal). Age distribution skews to infants/young children given early onset and historically high mortality.

10. Diagnostics

Clinical / laboratory tests:
Immunophenotyping (flow cytometry): Normal total T/B/NK counts (distinguishes from typical SCID) but reduced iNKT and Treg cells, altered γδ-T/NK subsets; poor in-vitro T-cell proliferation to mitogens/antigens [PMID: 29155098]. Immunoglobulins may be normal or with impaired specific antibody responses.
Functional Ca²⁺ assay (diagnostic gold standard for the mechanism): Absent SOCE on single-cell Ca²⁺ imaging of patient T cells/fibroblasts; absent I_CRAC by patch-clamp [In vitro; PMID: 29155098, 16582901].
ORAI1 protein expression: reduced/absent by Western blot/flow.
CBC (autoimmune cytopenias), Coombs test (AIHA), ferritin/triglycerides/sIL-2R (HLH work-up).
Sweat testing (anhidrosis); dental exam (enamel hypoplasia/amelogenesis imperfecta); muscle exam/CK (usually normal-to-mildly abnormal; hypotonia clinical).
Biomarkers: No circulating molecular biomarker; the functional SOCE defect and ORAI1 genotype are the definitive markers. LOINC codes apply to component tests (lymphocyte subsets, Ig levels).
Imaging / electrophysiology: No pathognomonic imaging. EMG/muscle biopsy may show non-specific/mild myopathic changes; patch-clamp electrophysiology (research) demonstrates absent CRAC current.
Biopsy/pathology: Sweat-gland biopsy shows structurally present but non-functional eccrine glands; tooth histology shows hypomineralized enamel.
Genetic testing (definitive):
Single-gene sequencing of ORAI1, or (preferred first-line today) primary-immunodeficiency gene panels or whole-exome sequencing (WES) / whole-genome sequencing (WGS) identifying biallelic ORAI1 LOF variants; confirm recessive segregation in parents [GTR/ClinVar].
CMA/karyotype/FISH: not indicated (no CNVs). mtDNA/repeat-expansion testing: not applicable.
Clinical criteria: No formal consensus criteria; diagnosis rests on the phenotypic tetrad + demonstration of absent SOCE + biallelic ORAI1 LOF.
Differential diagnosis: Classical SCID (usually low T-cell counts — ORAI1 has normal counts); STIM1-LOF CRAC channelopathy (indistinguishable clinically — test STIM1); NEMO/IKBKG (EDA-ID) and NFKBIA anhidrotic ectodermal dysplasia with immunodeficiency (distinct — PMID: 29155098 notes ORAI1 form is distinct); ALPS and other IPEX-like immunodysregulation for the autoimmune component; primary HLH genes (PRF1, UNC13D) when HLH is the presentation (PMID: 28633876).
Screening: No newborn TREC screening detection (T-cell numbers normal, so ORAI1 deficiency is typically MISSED by TREC-based newborn SCID screening — an important caveat). Cascade carrier testing in consanguineous families and prenatal/preimplantation testing where the familial variant is known.

11. Outcome / Prognosis

Survival / mortality: Historically poor without immune reconstitution — early death from overwhelming infection or fulminant autoimmunity/HLH is common in infancy/early childhood. With successful HSCT, immunological prognosis improves substantially.
Morbidity / function: Even after immune cure, patients retain lifelong anhidrosis (heat intolerance), dental enamel disease, and muscular hypotonia because these are non-hematopoietic and not corrected by HSCT — a key prognostic point (PMID: 26469693).
Complications: Opportunistic/severe infections; autoimmune hemolytic anemia and thrombocytopenia; lymphoproliferation; HLH (can be presenting and life-threatening, PMID: 28633876); dental morbidity; hyperthermia episodes.
Recovery potential: Immune compartment can be reconstituted (curative for infection/autoimmunity) via HSCT; non-immune features are permanent.
Prognostic factors: Age at diagnosis, severity/organ damage from infection before treatment, occurrence of HLH, and success/timing of HSCT. No validated molecular prognostic biomarker beyond genotype.

12. Treatment

(No ORAI1-specific approved drug exists; management is that of combined immunodeficiency with immunodysregulation. NCIT terms suggested.)

Definitive / curative:
Allogeneic hematopoietic stem cell transplantation (HSCT) — corrects the hematopoietic/immune defect (donor immune cells have wild-type ORAI1). Does not correct sweat-gland, dental, or muscle disease. NCIT: C15431 (Hematopoietic Stem Cell Transplantation). [Supported by disease-mechanism logic + CID management standards; PMID: 26469693]
Pharmacotherapy / supportive (symptom & complication management):
Immunoglobulin replacement (IVIG/SCIG) for antibody insufficiency — NCIT: C578 (Immunoglobulin Therapy).
Antimicrobial prophylaxis (e.g., trimethoprim-sulfamethoxazole against Pneumocystis; antifungal; antiviral) — NCIT: C15843 (Antibiotic Therapy).
Immunosuppression for autoimmunity/HLH (corticosteroids, and HLH-directed therapy e.g., etoposide-based protocols when HLH occurs) — NCIT: C15370 (Immunosuppressive Therapy).
Blood product/transfusion support for autoimmune cytopenias.
Advanced / experimental: Gene therapy / gene correction of ORAI1 in autologous HSCs is a conceptual future approach (not clinically available). No approved RNA/targeted/immunotherapy specific to ORAI1 deficiency. (Note: CRAC-channel inhibitors, e.g., under development for autoimmune/inflammatory disease, are the opposite pharmacology and are contraindicated conceptually here.)
Supportive / rehabilitative: Heat-avoidance and cooling strategies for anhidrosis; dental restoration/prosthodontics for enamel defects; physiotherapy for hypotonia; nutritional support.
Pharmacogenomics: Not applicable specifically; standard HSCT-conditioning PGx (e.g., thiopurine/TPMT, busulfan monitoring) applies generically.
Treatment algorithm: Early diagnosis → infection/autoimmune stabilization + prophylaxis + IVIG → definitive HSCT → lifelong management of non-immune (dental/sweat/muscle) features and heat precautions.

13. Prevention

Primary prevention: No way to prevent the genetic lesion. Genetic counseling for consanguineous couples/known carriers; carrier screening, prenatal diagnosis, and preimplantation genetic testing (PGT) where the familial ORAI1 variant is known.
Secondary prevention (early detection/treatment): Early clinical suspicion (infant with infections + anhidrosis + hypotonia + enamel defects) → SOCE functional assay + ORAI1 sequencing → early HSCT. Caveat: standard TREC newborn screening does not detect it (normal T-cell counts).
Tertiary prevention (complication reduction): Infection prophylaxis, IVIG, vaccination caution (avoid live vaccines in immunodeficient patients), aggressive management of autoimmunity/HLH, heat-precautions, dental care.
Immunization: Killed/inactivated vaccines per immunodeficiency guidelines; live vaccines contraindicated.
Counseling: Autosomal-recessive counseling — 25% recurrence risk per pregnancy for carrier couples; cascade testing of relatives.
Public-health/environmental: Not applicable (monogenic disease).

14. Other Species / Natural Disease

Taxonomy / orthologs: ORAI1 is conserved across vertebrates. Mouse Orai1 (NCBI Gene ID 109305; MGI:1925542), rat Orai1, zebrafish, and a Drosophila ortholog (Orai) exist — the pathway was in part dissected in Drosophila RNAi screens.
Natural disease in other species: A naturally occurring ORAI1-associated disorder in companion/wildlife species is not well documented in OMIA; the disease knowledge base is dominated by human patients and engineered animal models. (Not applicable / no strong natural-disease entry.)
Comparative biology: SOCE and the STIM–ORAI mechanism are evolutionarily conserved from insects to mammals, making cross-species mechanistic inference valid. Mouse SOCE loss reproduces immune phenotypes, supporting conserved mechanism.
Zoonotic potential / transmission: None (genetic, non-communicable).

15. Model Organisms

Mouse (primary model; Mus musculus, NCBI Taxon 10090):
Global Orai1 knockout: severe SOCE loss; reported perinatal lethality/reduced viability and small body size in some backgrounds, with immune defects — recapitulating the essentiality of CRAC channels. Surviving KO/knock-in models show impaired T-cell function.
Orai1 R93W knock-in (mouse equivalent of human R91W) models the human SCID allele.
Conditional/tissue-specific knockouts (e.g., Stim1/Stim2 double conditional; muscle-specific Orai1 KO) dissect cell-type roles — e.g., muscle-specific Orai1 deletion abolishes muscle SOCE (PMID: 35939054), and Stim1/Stim2-deleted macrophages/DCs surprisingly retain many effector functions, showing lineage-specific SOCE dependence (PMID: 26109647).
Model types available: knockout, knock-in (point mutant), conditional/floxed, tissue-specific — via MGI/IMPC/KOMP.
In vitro / cellular models: Patient-derived T cells and fibroblasts (absent SOCE/I_CRAC) are the definitive human cellular models [PMID: 29155098, 16582901]; heterologous ORAI1/STIM1 expression systems (HEK293) and concatenated tetramer constructs quantify gene-dosage effects of R91W [PMID: 19075015]. Ameloblast/enamel-cell models illustrate CRAC-dependent mineralization (PMID: 30114531).
Invertebrate: Drosophila Orai/Stim genetic screens established the pathway.
Phenotype recapitulation: Mouse and patient-cell models faithfully reproduce the SOCE/immune defect; mouse models capture immune and muscle phenotypes well.
Model limitations: Complete global Orai1 KO can be perinatally lethal in mice (more severe than the human hypomorphic/viable phenotype), and murine ectodermal (sweat/enamel) and autoimmune features may not fully phenocopy the human tetrad; paralog compensation differs between species.
Resources: MGI (Orai1 MGI:1925542), IMPC/KOMP, IMSR for strain availability; ZFIN (zebrafish), FlyBase (Drosophila Orai).

Supported vs Refuted Hypotheses

SUPPORTED: ORAI1 LOF → abolished SOCE → NFAT-signaling failure → combined immunodeficiency (PMID: 16582901, 17572487, 26469693). ✔
SUPPORTED: ORAI1 loss reduces iNKT/Treg cells → autoimmunity/immunodysregulation (PMID: 29155098, 28633876). ✔
SUPPORTED: Multisystem (sweat gland, dental enamel, muscle) involvement reflects SOCE dependence of those tissues (PMID: 26469693, 30114531). ✔
SUPPORTED: Recessive with dosage-dependent channel function (heterozygotes subclinical) (PMID: 19075015). ✔
CONTRAST/REFUTED as same disease: Gain-of-function ORAI1 is NOT "ORAI1 deficiency"; it causes dominant TAM/Stormorken (PMID: 26469693). ✔ (kept distinct)

Limitations & Future Directions

Ultra-rare disease: all clinical claims rest on small case series; no registry-level epidemiology, QoL, or survival statistics exist. Prevalence, penetrance-by-feature, and long-term HSCT outcomes are under-quantified.
Some branch mechanisms (sweat gland, enamel) are inferred from tissue SOCE dependence and mouse data rather than proven in human tissue in vivo.
Future: prospective natural-history registries; gene-correction/gene-therapy proof-of-concept; therapies for the non-hematopoietic (dental/sweat/muscle) features not addressed by HSCT.

Evidence key PMIDs: 16582901 (Feske 2006, first ORAI1 SCID mutation), 29155098 (novel recessive ORAI1 mutations, subset deficits), 26469693 (Lacruz & Feske review, disease definition & GOF contrast), 17572487 (SOCE–NFAT axis), 19075015 (heterozygous gene-dosage), 28633876 (HLH presentation), 30114531 (enamel/CRAC), 26109647 (innate-cell SOCE dependence, mouse), 35939054 (muscle-specific Orai1 KO), 29635109 (ion channelopathies of immune system review).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	13
On topic	11
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	39
Resolved	37
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	20
Terms named correctly	14
Terms named as a different term	1
Terms whose name is worth a second look	5

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:

UBERON:0001820 (1 mention) - the report calls it "integument/skin adnexa — eccrine sweat glands"; UBERON calls it sweat gland

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:

CL:0000921 (2 mentions) - the report calls it "NKT cell"; CL calls it type I NK T cell, and lists "type I NKT cell" among its other names
CL:0002064 (2 mentions) - the report calls it "ameloblast/enamel-forming cell"; CL calls it pancreatic acinar cell
CL:0000188 (2 mentions) - the report calls it "skeletal muscle cell"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
UBERON:0001134 (1 mention) - the report calls it "skeletal muscle"; UBERON calls it skeletal muscle tissue, and lists "skeletal muscle" among its other names
CL:0000623 (1 mention) - the report calls it "NK cell"; CL calls it natural killer cell, and lists "NK cell" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.

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ORAI1 Deficiency (CRAC Channelopathy) — Disease Characterization Report

Summary / Consensus Answer

1. Disease Information

2. Etiology

Disease Causal Factors

Risk Factors

Protective Factors

Gene–Environment Interactions

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Category detail

Suggested ontology terms

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

Supported vs Refuted Hypotheses

Limitations & Future Directions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Prefixes with no resolver