CALR Gene (Calreticulin): Structure, Function, and Clinical Significance
A comprehensive overview of the CALR gene, its protein product calreticulin, associated diseases, expression patterns, and mutations.
Gene Information Card
| Symbol | CALR |
|---|---|
| Full Name | Calreticulin |
| Gene Type | Protein coding |
| Chromosomal Location | 19p13.13 |
| NCBI Gene ID | 811 ncbi.nlm.nih.gov/gene/811 |
| Ensembl ID | ENSG00000179218 |
| UniProt ID | P27797 |
| OMIM ID | 109091 |
| HGNC ID | 1455 |
| Aliases | CRT, CALRUL, SICCA, RO, cC1qR |
Description
The CALR gene encodes calreticulin, a multifunctional calcium-binding chaperone protein primarily located in the endoplasmic reticulum (ER). Calreticulin plays critical roles in calcium homeostasis, protein folding, and quality control within the ER. It also participates in immune responses, including antigen presentation and clearance of apoptotic cells. Mutations in CALR are recurrent in myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia (ET) and primary myelofibrosis (PMF), leading to constitutive activation of the thrombopoietin receptor (MPL) and downstream JAK-STAT signaling.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Essential Thrombocythemia (ET) | Somatic mutations in exon 9 of CALR result in a frameshift that generates a novel C-terminal peptide, which binds to and activates MPL, leading to constitutive JAK-STAT signaling and increased platelet production. | COSMIC, ClinVar, PMID: 23883322 |
| Primary Myelofibrosis (PMF) | Similar to ET, CALR mutations cause MPL activation, promoting megakaryocyte proliferation and fibrosis in the bone marrow. | COSMIC, ClinVar, PMID: 23883322 |
| Myeloproliferative Neoplasms (MPN) - general | CALR mutations are one of the three driver mutations (along with JAK2 and MPL) in Philadelphia-negative MPNs, contributing to clonal hematopoiesis. | COSMIC, ClinVar, PMID: 23883322 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 12.5 | Medium |
| Bone Marrow | 10.2 | Medium |
| Spleen | 9.8 | Medium |
| Lung | 8.5 | Medium |
| Kidney | 7.9 | Low |
| Brain | 5.1 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| K562 (Chronic myelogenous leukemia) | 15.3 | High expression |
| HEK293 (Embryonic kidney) | 12.8 | Medium expression |
| HeLa (Cervical carcinoma) | 11.5 | Medium expression |
| MCF7 (Breast carcinoma) | 9.2 | Medium expression |
| HepG2 (Hepatocellular carcinoma) | 8.7 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Type 1 (52-bp deletion) | Frameshift deletion | ~50% of CALR-mutated MPN cases | Generates a novel C-terminal peptide that activates MPL; associated with higher risk of myelofibrosis |
| Type 2 (5-bp insertion) | Frameshift insertion | ~40% of CALR-mutated MPN cases | Also activates MPL but with weaker signaling; associated with lower risk of thrombosis |
| Other variants | Various frameshift mutations | ~10% of CALR-mutated MPN cases | All lead to loss of the KDEL ER-retention signal and gain of a novel peptide that binds MPL |
Mutation functional classification
Loss of Function (LOF)
Not typically loss-of-function; CALR mutations are gain-of-function in the context of MPL activation.
Gain of Function (GOF)
CALR mutations are gain-of-function: the mutant protein acquires the ability to bind and activate MPL, leading to constitutive JAK-STAT signaling.
Dominant Negative (DN)
Not applicable; CALR mutations are heterozygous and act as dominant gain-of-function alleles.
View complete mutation data：
Gene Ontology (GO)
| • Calcium ion binding | • Chaperone binding |
| • Protein folding | • Endoplasmic reticulum lumen |
| • Response to endoplasmic reticulum stress | • Antigen processing and presentation |
| • Apoptotic cell clearance |
Pathways
• JAK-STAT signaling pathway
• Calcium signaling pathway
• Protein processing in endoplasmic reticulum
• Antigen processing and presentation
Protein Summary
Calreticulin is a 46 kDa soluble protein with three domains: N-domain (chaperone activity), P-domain (calcium binding), and C-domain (calcium storage and ER retention). It is highly conserved and expressed in all nucleated cells. In the ER, calreticulin assists in protein folding and quality control, preventing aggregation of misfolded proteins. It also regulates calcium homeostasis by binding calcium with high capacity. In addition, calreticulin is found on the cell surface and in the extracellular space, where it mediates immune functions such as phagocytosis of apoptotic cells and antigen presentation. Mutant calreticulin in MPNs loses its ER retention signal and is secreted, but it still binds to MPL on the cell surface, leading to receptor dimerization and activation.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CALR Knockout HEK293 Cell Line | EDJ-KQ3567 | Human | 811 | Details Get a Quote |
| CALR3 Knockout HEK293 Cell Line | EDJ-KQ8842 | Human | 125972 | Details Get a Quote |
| CALR Knockout A-549 Cell Line | EDJ-KQ25434 | Human | 811 | Details Get a Quote |
| CALR Knockout HCT 116 Cell Line | EDJ-KQ25435 | Human | 811 | Details Get a Quote |
| CALR Knockout HeLa Cell Line | EDJ-KQ25436 | Human | 811 | Details Get a Quote |
| CALR3 Knockout HeLa Cell Line | EDJ-KQ58159 | Human | 125972 | Details Get a Quote |
| CALR3 Knockout A-549 Cell Line | EDJ-KQ66644 | Human | 125972 | Details Get a Quote |
| CALR3 Knockout HCT 116 Cell Line | EDJ-KQ75064 | Human | 125972 | Details Get a Quote |
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