FCER1A Human
Description
Gene Structure and Transcription
The FCER1A gene (ENSG00000179639) is located on chromosome 1 (159,289,714–159,308,224) and encodes three splice variants (Table 1) . A co-expressed natural antisense RNA (FCER1A-AS) regulates its expression in cis, as shown by CRISPR/RfxCas13d knockout studies .
| Transcript ID | Length (bp) | Protein (aa) | Biotype |
|---|---|---|---|
| ENST00000693622.1 | 1,073 | 257 | Protein coding |
| ENST00000368115.5 | 1,165 | 257 | Protein coding |
| ENST00000368114.1 | 765 | 224 | Protein coding |
Table 1: FCER1A gene transcripts and their characteristics .
Protein Characteristics
FCER1A is a glycosylated transmembrane protein with an immunoglobulin-like domain. Recombinant forms (e.g., HEK293-expressed) include a C-terminal 6His-tag and are used in functional studies . Key features:
| Property | Value | Source |
|---|---|---|
| Molecular Weight | 21.8 kDa (recombinant fragment) | ProspecBio |
| Glycosylation | Yes | |
| Binding Affinity | ≤0.01 µg/mL (IgE) | |
| Purification | Chromatography |
Table 2: Key properties of recombinant FCER1A protein .
Biological Function and Signaling
FCER1A forms a tetramer with β and γ subunits (FcεRI) to mediate IgE-dependent responses. Crosslinking triggers:
-
Cell Activation: Release of histamine, cytokines, and leukotrienes .
-
Signaling Pathways: ITAM-mediated phosphorylation via β and γ subunits .
In FCER1A-AS-deficient mice, FCER1A expression is abolished, mirroring FcεRI knockout phenotypes (e.g., impaired cutaneous anaphylaxis) .
Role in Diseases
FCER1A dysregulation is linked to:
-
Allergic Disorders: Asthma, atopic dermatitis, and chronic urticaria .
-
Immune-Mediated Diseases: Autoimmune conditions and parasitic infections (e.g., Schistosoma japonicum) .
Antisense RNA Regulation
FCER1A-AS is essential for FCER1A sense transcript stability and translation. Its knockout eliminates IgE-mediated responses, as shown in MC/9 mast cells and in vivo models .
Knockout and Phenotypic Studies
| Model | Phenotype | Outcome |
|---|---|---|
| FCER1A-KO mice | No FcεRI expression | Reduced survival in S. japonicum infection |
| FCER1A-AS-deficient mice | No FCER1A expression | Absent IgE-mediated anaphylaxis |
Table 3: Phenotypic comparisons of FCER1A and antisense RNA knockout models .
Therapeutic and Research Applications
Product Specs
Q&A
What is FCER1A and what is its role in the human immune system?
FCER1A (Fc fragment of IgE high affinity I receptor alpha polypeptide) encodes the alpha subunit of the high-affinity IgE receptor (FcεRI). This receptor is crucial for initiating allergic responses. The FCER1A protein binds to the Fc region of immunoglobulin E (IgE) with high affinity. When allergens cross-link receptor-bound IgE molecules, cell activation occurs, leading to the release of mediators such as histamine that are responsible for allergic manifestations. Additionally, the receptor induces the secretion of important lymphokines .
What is the molecular structure and location of the FCER1A gene and protein?
The FCER1A gene is located on chromosome 1q23 (1:159259504-159278014) in humans . The encoded protein has a molecular mass of approximately 29.6 kilodaltons and contains two extracellular IgE-like domains . The complete high-affinity IgE receptor complex consists of an alpha subunit (encoded by FCER1A), a beta subunit, and two gamma subunits, forming a tetrameric structure that functions in IgE-mediated allergic responses .
Which cell types express FCER1A and how can it be used as a cell marker?
FCER1A is expressed in several immune cell types and can serve as an identification marker for specific cell populations. The FCER1A marker is particularly useful for identifying Type 2 Dendritic (DC2) Cells, Type 3 Dendritic (DC3) Cells, and Early Megakaryocytes (MK) . Expression patterns can be analyzed using techniques such as flow cytometry, immunohistochemistry, or single-cell RNA sequencing to distinguish these cell populations in research contexts.
Which FCER1A polymorphisms have been associated with IgE levels in human populations?
Several genome-wide association studies have identified FCER1A polymorphisms that influence total serum IgE levels. The most consistently associated variants include rs2511211, rs2427837, and rs2251746, which are in high linkage disequilibrium (mean r > 0.8) . These polymorphisms have demonstrated significant associations with serum IgE levels in general population studies, with p-values as low as 4.37 × 10⁻⁶ . A functional promoter variant affecting FCER1A expression (rs2251746) has been replicated in over 10,000 individuals across four independent population-based cohorts .
Do FCER1A polymorphisms affect IgE levels differently in asthmatics versus non-asthmatics?
Research has demonstrated distinct patterns of association between FCER1A polymorphisms and IgE levels in asthmatics compared to non-asthmatics. While the polymorphisms rs2511211, rs2427837, and rs2251746 show strong associations in both groups, they exhibit the strongest effect in non-asthmatics (lowest p = 0.0003) . Interestingly, additional polymorphisms (rs3845625, rs7522607, and rs2427829) demonstrate significant associations with total serum IgE specifically in asthmatic populations (lowest p = 0.01) . This suggests that different genetic mechanisms may be at play in regulating IgE levels in individuals with asthma versus those without.
| Group | Polymorphism | Association in Non-asthmatics | Association in Asthmatics |
|---|---|---|---|
| Primary variants | rs2511211, rs2427837, rs2251746 | Strongest (p = 0.0003) | Present but weaker (p = 0.003) |
| Secondary variants | rs3845625, rs7522607, rs2427829 | Not significant | Significant (p = 0.01) |
What is the relationship between FCER1A polymorphisms and allergic rhinitis?
Despite the established role of FCER1A in allergic responses, research has produced conflicting results regarding its association with allergic rhinitis (AR). A case-control study conducted in a Han Chinese population failed to find significant associations between 16 selected SNPs in the FCER1A gene region and allergic rhinitis susceptibility . This study included 378 patients with AR and 288 healthy controls but did not detect associations even in subgroup analyses for different allergen sensitivities. The polymorphisms studied included rs2494262, rs2427837, and rs2251746, with no significant differences in allele frequencies between patients and controls .
What is the mechanism by which FCER1A initiates allergic responses?
The allergic response mechanism through FCER1A follows a sequence of molecular events:
-
The alpha subunit of FcεRI (encoded by FCER1A) binds to the Fc portion of IgE antibodies with high affinity
-
When an allergen cross-links two or more receptor-bound IgE molecules, it triggers receptor aggregation
-
This aggregation initiates intracellular signaling cascades involving immunoreceptor tyrosine-based activation motifs (ITAMs)
-
The signaling results in mast cell or basophil degranulation and release of inflammatory mediators such as histamine, leukotrienes, and cytokines
-
These mediators produce the symptoms associated with allergic reactions
The complete receptor complex requires interaction with other subunits, particularly FCER1G (gamma chain) and MS4A2 (beta chain), to effectively transduce signals following allergen binding .
How does FCER1A interact with other proteins in immune signaling pathways?
FCER1A participates in a complex protein interaction network to facilitate immune signaling. Key interaction partners include:
-
FCER1G (FcεRI gamma chain): An adapter protein containing immunoreceptor tyrosine-based activation motifs (ITAMs) that transduces activation signals. This interaction has the highest confidence score (0.997) and is essential for allergic inflammatory signaling in mast cells .
-
MS4A2 (FcεRI beta chain): Forms part of the high-affinity IgE receptor complex. Aggregation of the complete receptor by multivalent antigens is required for the full mast cell response, including degranulation and production of lipid mediators and cytokines (confidence score: 0.996) .
-
SYK (Spleen tyrosine kinase): A non-receptor tyrosine kinase that mediates signal transduction downstream of the activated receptor complex .
These interactions can be studied using co-immunoprecipitation, yeast two-hybrid systems, or proximity ligation assays to understand the dynamics of receptor complex formation during allergic responses.
What are the most effective methods for studying FCER1A expression in different cell types?
Multiple complementary approaches can be used to effectively study FCER1A expression:
-
Flow Cytometry: Using fluorescently labeled anti-FCER1A antibodies to quantify expression levels on the cell surface of individual cells. This method allows for simultaneous assessment of multiple markers to identify specific cell populations expressing FCER1A.
-
Immunohistochemistry/Immunofluorescence: For visualizing FCER1A expression in tissue contexts, maintaining spatial relationships between different cell types.
-
Quantitative PCR (qPCR): For measuring FCER1A mRNA expression levels in sorted cell populations or tissue samples.
-
Single-cell RNA Sequencing: Provides comprehensive expression profiles at single-cell resolution, allowing identification of cell types expressing FCER1A and co-expression patterns with other genes.
-
Western Blotting: For detecting and semi-quantifying FCER1A protein expression in cell or tissue lysates.
When selecting antibodies for these applications, researchers should choose validated reagents with demonstrated specificity for human FCER1A, as 754 different anti-FCER1A antibody products are available across 32 suppliers .
What are the recommended approaches for genotyping FCER1A polymorphisms?
Based on published research methodologies, effective approaches for FCER1A polymorphism genotyping include:
-
Microarray-based Genotyping: Studies have successfully used platforms like the Illumina HumanHap300Chip for genotyping polymorphisms such as rs2511211, rs2427837, and rs2251746 .
-
MALDI-TOF Mass Spectrometry: This technique has been employed for accurate genotyping of multiple FCER1A polymorphisms in large cohort studies .
-
PCR-RFLP (Restriction Fragment Length Polymorphism): A cost-effective method for genotyping specific known polymorphisms when analyzing fewer variants.
-
TaqMan Assays: Provides high-throughput capabilities with good accuracy for known SNPs.
-
Next-Generation Sequencing: For comprehensive analysis of all variants within the FCER1A gene region, particularly when investigating novel polymorphisms.
When designing a genotyping strategy, researchers should consider coverage of both promoter and coding regions, as functional variants have been identified in both areas of the FCER1A gene.
How can researchers resolve contradictory findings about FCER1A polymorphisms in different populations?
The contradictory findings regarding FCER1A polymorphisms across different populations present a complex research challenge. To address these inconsistencies, researchers should consider:
-
Population Stratification Analysis: Implement statistical methods to account for underlying population structure that might confound genetic associations.
-
Meta-analysis Approaches: Combine data from multiple studies with appropriate statistical adjustments for heterogeneity to increase power and identify consistent effects.
-
Functional Validation: Move beyond association studies to examine the molecular consequences of identified polymorphisms using reporter assays, EMSA (Electrophoretic Mobility Shift Assay), or CRISPR-based approaches.
-
Environmental Interaction Analysis: Investigate gene-environment interactions that might explain why certain polymorphisms show effects in some populations but not others.
-
Epistasis Evaluation: Examine potential interactions between FCER1A polymorphisms and variants in other genes involved in IgE regulation or allergic response pathways.
The contradictory results between studies in different populations (e.g., European cohorts versus Han Chinese) might reflect genuine biological differences in genetic architecture or result from methodological variations in phenotype definition, sample size limitations, or environmental factors .
What are the current experimental models for studying FCER1A function in human allergy?
Advanced experimental models for investigating human FCER1A function include:
-
Primary Human Mast Cell and Basophil Cultures: Isolated from peripheral blood or tissues to study receptor signaling in the most physiologically relevant context.
-
Patient-derived Induced Pluripotent Stem Cells (iPSCs): Can be differentiated into mast cells or basophils to study how genetic variants affect receptor function in a patient-specific manner.
-
Humanized Mouse Models: Mice engineered to express human FCER1A for in vivo studies of receptor function and potential therapeutic interventions.
-
CRISPR/Cas9 Gene Editing: To introduce specific FCER1A variants into cell lines or primary cells for functional studies.
-
Ex vivo Allergen Challenge Models: Using blood or tissue samples from allergic and non-allergic individuals to study the dynamics of FCER1A-mediated responses to specific allergens.
-
Organoid and 3D Culture Systems: Recreating tissue microenvironments to study FCER1A function in a context that better mimics in vivo conditions.
Each model system has strengths and limitations, and combining multiple approaches often provides the most comprehensive understanding of FCER1A biology in human allergic responses.
How might epigenetic regulation affect FCER1A expression and function in allergic disease?
Epigenetic regulation of FCER1A represents an emerging area of research with potential implications for allergic disease mechanisms:
-
DNA Methylation: Methylation patterns in the FCER1A promoter region may influence gene expression levels. Researchers can investigate this using bisulfite sequencing or methylation-specific PCR in samples from allergic versus non-allergic individuals.
-
Histone Modifications: Chromatin immunoprecipitation (ChIP) assays can identify histone marks associated with active or repressed FCER1A expression in different cell types or disease states.
-
microRNA Regulation: FCER1A mRNA may be subject to post-transcriptional regulation by microRNAs. Computational prediction followed by luciferase reporter assays can validate such interactions.
-
Chromatin Accessibility: Techniques like ATAC-seq can reveal differences in chromatin structure around the FCER1A locus that may correlate with expression changes in allergic disease.
-
Long Non-coding RNAs: These may act as scaffolds or decoys affecting FCER1A transcription and can be studied through RNA immunoprecipitation and functional knockdown experiments.
Understanding the epigenetic landscape of FCER1A could explain variability in allergic phenotypes not accounted for by genetic polymorphisms alone and potentially identify new therapeutic targets for allergic diseases.
What is the potential of FCER1A as a therapeutic target for allergic diseases?
FCER1A represents a promising therapeutic target due to its central role in initiating allergic responses. Current and emerging strategies include:
-
Anti-FCER1A Antibodies: Antibodies that block IgE binding to FCER1A without triggering receptor crosslinking could prevent mast cell and basophil activation.
-
Receptor Expression Modulators: Compounds that downregulate FCER1A expression might reduce allergic sensitivity. This approach could leverage knowledge of the genetic variants that naturally affect expression levels.
-
Peptide Inhibitors: Designed peptides that interfere with the assembly of the receptor complex or its interaction with signaling molecules.
-
Gene Therapy Approaches: CRISPR-based approaches to modify FCER1A expression or function in target cells.
-
Small Molecule Inhibitors: Targeting either the receptor itself or downstream signaling molecules specific to the FCER1A pathway.
The effectiveness of these approaches may vary based on individual genetic profiles, particularly the FCER1A polymorphisms associated with IgE levels and allergic phenotypes .
How can FCER1A polymorphism data be integrated into personalized approaches to allergy treatment?
Integration of FCER1A genetic information into personalized medicine approaches could involve:
-
Pharmacogenetic Profiling: Screening for FCER1A polymorphisms that predict response to anti-IgE therapies like omalizumab.
-
Risk Stratification: Using polymorphism data from rs2511211, rs2427837, and rs2251746 to identify individuals at higher risk for developing IgE-mediated allergies .
-
Differential Approaches for Asthmatic vs. Non-asthmatic Allergies: Given the different patterns of association in these groups, treatment strategies might be tailored accordingly .
-
Integration with Other Genetic Markers: Combining FCER1A data with other genetic variants involved in allergic response for more comprehensive risk assessment.
-
Biomarker Development: Developing assays that measure the functional consequences of FCER1A variants to guide treatment decisions.
Product Science Overview
Fc-Epsilon RI-Alpha (FcεRIα) is a high-affinity receptor for the Fc region of immunoglobulin E (IgE), an antibody isotype involved in allergic reactions and immunity against parasites . This receptor plays a crucial role in the allergic response by binding to IgE and triggering the release of inflammatory mediators from mast cells and basophils .
FcεRI is a tetrameric receptor complex composed of one alpha (α) chain, one beta (β) chain, and two gamma (γ) chains . The alpha chain (FcεRIα) is responsible for binding to the Fc region of IgE . This binding is essential for the receptor’s role in mediating allergic responses. When an allergen cross-links IgE bound to FcεRIα on the surface of mast cells or basophils, it triggers a cascade of signaling events leading to the release of histamine and other inflammatory mediators .
Recombinant FcεRIα is typically produced using mammalian cell expression systems, such as Chinese Hamster Ovary (CHO) cells or mouse myeloma cells . These systems are chosen for their ability to perform post-translational modifications, which are crucial for the proper folding and function of the protein. The recombinant protein is often tagged with a His-tag or Avi-tag to facilitate purification and detection .
The production of recombinant FcεRIα involves several key steps:
- Gene Cloning: The gene encoding FcεRIα is cloned into an expression vector suitable for the chosen mammalian cell system.
- Transfection: The expression vector is introduced into the mammalian cells using methods such as electroporation or lipid-mediated transfection.
- Selection and Expansion: Transfected cells are selected using antibiotic resistance markers and expanded in culture to produce large quantities of the recombinant protein.
- Purification: The recombinant protein is purified from the culture supernatant using affinity chromatography techniques, such as nickel affinity chromatography for His-tagged proteins .
FcεRIα’s interaction with IgE is a critical aspect of its function. The binding affinity between FcεRIα and IgE is extremely high, which ensures that even low concentrations of IgE can trigger an allergic response . This high-affinity binding is mediated by specific interactions between the Fc region of IgE and the extracellular domain of FcεRIα . The cross-linking of IgE-FcεRIα complexes by allergens leads to the activation of intracellular signaling pathways, resulting in the release of histamine and other mediators .
