ORAI1: The Calcium Release-Activated Calcium Channel Pore-Forming Subunit
A critical regulator of store-operated calcium entry, immune signaling, and muscle physiology; mutations cause immune and skeletal disorders.
Gene Information Card
| Symbol | ORAI1 |
|---|---|
| Full Name | ORAI calcium release-activated calcium modulator 1 |
| Gene Type | protein coding |
| Chromosomal Location | 12q24.31 |
| NCBI Gene ID | 84876 ncbi.nlm.nih.gov/gene/84876 |
| Ensembl ID | ENSG00000276045 |
| UniProt ID | Q96D31 |
| OMIM ID | 610277 |
| HGNC ID | 25896 |
| Aliases | CRACM1, IMD9, ORAT1, TAM2, FLJ14466 |
Description
ORAI1 encodes the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, which mediates store-operated calcium entry (SOCE) following depletion of endoplasmic reticulum (ER) calcium stores. This process is essential for immune cell activation, muscle contraction, and other calcium-dependent signaling pathways. Mutations in ORAI1 lead to primary immunodeficiency with muscular hypotonia and tubular aggregate myopathy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Immunodeficiency 9 (IMD9) | Loss-of-function mutations impair SOCE, leading to defective T-cell and B-cell activation, causing severe combined immunodeficiency-like phenotype. | OMIM #612782; PMID: 19633662 |
| Tubular aggregate myopathy (TAM2) | Gain-of-function mutations increase CRAC channel activity, causing excessive calcium influx, leading to muscle fiber damage and tubular aggregates. | OMIM #615883; PMID: 28132602 |
| Stormorken syndrome | Gain-of-function mutations in ORAI1 (or STIM1) cause a syndrome with thrombocytopenia, anemia, and myopathy due to constitutive calcium entry. | OMIM #185070; PMID: 28132602 |
| Autoimmune diseases (susceptibility) | Polymorphisms in ORAI1 may alter SOCE, contributing to autoimmune conditions like rheumatoid arthritis and multiple sclerosis. | PMID: 22005931 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lymph node | 14.2 | High |
| Spleen | 12.5 | High |
| Thymus | 10.8 | High |
| Bone marrow | 8.3 | Medium |
| Skeletal muscle | 6.1 | Medium |
| Lung | 4.5 | Low |
| Brain | 2.0 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Jurkat (T-cell leukemia) | 18.5 | High expression; used in SOCE studies |
| HEK293 (embryonic kidney) | 12.0 | Commonly used for heterologous expression |
| HeLa (cervical carcinoma) | 9.8 | Moderate expression |
| K562 (chronic myelogenous leukemia) | 7.2 | Low to moderate |
| A549 (lung carcinoma) | 3.4 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.R91W | Missense | Rare (found in IMD9 families) | Loss-of-function; disrupts pore function, abolishes SOCE |
| p.A103E | Missense | Rare (found in TAM2) | Gain-of-function; increases channel activity |
| p.G98S | Missense | Rare (found in TAM2) | Gain-of-function; enhances calcium influx |
| p.L194P | Missense | Rare (found in IMD9) | Loss-of-function; impairs channel trafficking |
| c.574+1G>A | Splice site | Rare (found in IMD9) | Loss-of-function; causes exon skipping and truncated protein |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., p.R91W) impair CRAC channel function, leading to defective SOCE and immune deficiency.
Gain of Function (GOF)
Gain-of-function mutations (e.g., p.A103E, p.G98S) increase CRAC channel activity, causing excessive calcium entry and myopathy.
Dominant Negative (DN)
Some ORAI1 mutations may exert dominant-negative effects by forming non-functional heteromeric channels with wild-type subunits, though this is less documented.
View complete mutation data：
Gene Ontology (GO)
| • calcium release-activated calcium channel activity | • store-operated calcium channel activity |
| • calcium ion transmembrane transport | • plasma membrane |
| • integral component of membrane | • response to endoplasmic reticulum stress |
| • positive regulation of T cell activation | • positive regulation of NFAT protein import into nucleus |
Pathways
• Calcium signaling pathway (KEGG hsa04020)
• T cell receptor signaling pathway (KEGG hsa04660)
• B cell receptor signaling pathway (KEGG hsa04662)
• Fc epsilon RI signaling pathway (KEGG hsa04664)
• Store-operated calcium entry (Reactome: R-HSA-1237044)
Protein Summary
ORAI1 is a 301-amino acid plasma membrane protein with four transmembrane domains. It forms hexameric channels that are activated by STIM1 upon ER calcium store depletion. The channel is highly selective for Ca2+ and essential for sustained calcium influx in immune cells. Structural studies reveal a selectivity filter formed by acidic residues in the pore region. ORAI1 also interacts with other proteins like CRACR2A to modulate channel activity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ORAI1 Knockout HEK293 Cell Line | EDJ-KQ1567 | Human | 84876 | Details Get a Quote |
| ORAI1 Knockout A-549 Cell Line | EDJ-KQ21246 | Human | 84876 | Details Get a Quote |
| ORAI1 Knockout HCT 116 Cell Line | EDJ-KQ21247 | Human | 84876 | Details Get a Quote |
| ORAI1 Knockout HeLa Cell Line | EDJ-KQ21248 | Human | 84876 | Details Get a Quote |
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