HLA-C Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the HLA-C gene, including its genomic organization, protein function, associated diseases, expression patterns, and clinical relevance.
Gene Information Card
| Symbol | HLA-C |
|---|---|
| Full Name | Major Histocompatibility Complex, Class I, C |
| Gene Type | Protein-coding |
| Chromosomal Location | 6p21.33 (GRCh38) |
| NCBI Gene ID | 3107 ncbi.nlm.nih.gov/gene/3107 |
| Ensembl ID | ENSG00000204525 |
| UniProt ID | P10321 |
| OMIM ID | 142840 |
| HGNC ID | HGNC:4933 |
| Aliases | HLA-Cw, HLA-JY3, D6S204, PSORS1 |
Description
HLA-C is a classical class I major histocompatibility complex (MHC) gene located in the human leukocyte antigen (HLA) region on chromosome 6p21.33. It encodes a heavy chain that forms a heterodimer with beta-2-microglobulin to present peptides to cytotoxic T lymphocytes and natural killer (NK) cells. HLA-C is highly polymorphic, with over 4,000 known alleles, and plays a critical role in immune surveillance, transplantation compatibility, and disease susceptibility. Its expression is regulated by microRNAs and transcription factors, and it is implicated in viral infections, autoimmune diseases, and cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| HIV/AIDS | HLA-C expression levels influence viral load control; certain alleles (e.g., C*04) are associated with poor control, while others (e.g., C*01) with better outcomes. The mechanism involves NK cell regulation via KIR ligands. | Genome-wide association studies (GWAS) and functional studies (e.g., International HIV Controllers Study, 2010) |
| Psoriasis | HLA-Cw6 (C*06:02) is a major risk allele for early-onset psoriasis. The mechanism involves presentation of autoantigens to T cells, leading to skin inflammation. | Multiple case-control studies and meta-analyses (e.g., Nair et al., 2009) |
| Crohn's Disease | HLA-C variants are associated with altered immune responses to gut microbiota, contributing to chronic inflammation. | GWAS and immunochip studies (e.g., Jostins et al., 2012) |
| Cervical Cancer | HLA-C alleles may affect HPV clearance and immune surveillance, influencing cancer risk. | Case-control studies (e.g., Madeleine et al., 2008) |
| Transplant Rejection | HLA-C mismatches between donor and recipient can trigger T-cell and NK-cell alloreactivity, leading to graft rejection or graft-versus-host disease. | Clinical transplantation studies and registries (e.g., UNOS data) |
| Autoimmune Diseases (e.g., Type 1 Diabetes) | HLA-C alleles may contribute to autoimmune risk by presenting self-peptides that cross-react with microbial antigens. | Association studies (e.g., Noble et al., 2002) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Blood | 12.5 | High |
| Spleen | 10.2 | High |
| Lymph Node | 9.8 | High |
| Bone Marrow | 8.5 | Medium |
| Lung | 6.3 | Medium |
| Liver | 4.1 | Low |
| Brain | 1.2 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 15.3 | High expression; used in immunology studies |
| K562 (leukemia) | 2.1 | Low expression; HLA-C is silenced in this cell line |
| Jurkat (T-cell leukemia) | 8.7 | Moderate expression; relevant for T-cell signaling |
| HUVEC (endothelial) | 5.4 | Moderate expression; important for transplantation studies |
| THP-1 (monocyte) | 11.2 | High expression; monocytic lineage |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| C*06:02 (rs1131111) | Allelic variant | ~10% in European populations | Associated with psoriasis; alters peptide-binding groove |
| C*04:01 (rs1142345) | Allelic variant | ~15% in African populations | Associated with HIV control; affects NK cell regulation |
| C*07:01 (rs10484554) | Allelic variant | ~20% in European populations | Common allele; associated with autoimmune diseases |
| C*02:02 (rs1050458) | Allelic variant | ~5% in Asian populations | Linked to altered immune response to infections |
| C*05:01 (rs1131122) | Allelic variant | ~8% in global populations | Associated with transplant outcomes |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in HLA-C are rare due to essential immune functions. Complete loss would lead to severe immunodeficiency and impaired NK cell education. Some alleles may have reduced cell surface expression due to promoter variants, but these are not classified as complete loss-of-function.
Gain of Function (GOF)
Gain-of-function mutations are not well-defined for HLA-C. However, certain alleles may have enhanced peptide presentation or altered KIR binding, leading to stronger immune responses, which could be considered a functional gain.
Dominant Negative (DN)
Dominant-negative effects are not typical for HLA-C, as it is a cell surface receptor. However, some alleles may produce misfolded proteins that interfere with the assembly of other MHC class I molecules, but this is not a classic dominant-negative mechanism.
View complete mutation data：
Gene Ontology (GO)
| • MHC class I protein complex | • Peptide antigen binding |
| • Immune response | • Antigen processing and presentation of exogenous peptide antigen via MHC class I |
| • Cell surface receptor signaling pathway | • Regulation of natural killer cell mediated immunity |
Pathways
• Antigen processing and presentation (KEGG hsa04612)
• Natural killer cell mediated cytotoxicity (KEGG hsa04650)
• Allograft rejection (KEGG hsa05330)
• Graft-versus-host disease (KEGG hsa05332)
• Type I diabetes mellitus (KEGG hsa04940)
Protein Summary
The HLA-C protein is a 366-amino-acid type I transmembrane glycoprotein with three extracellular domains (α1, α2, α3), a transmembrane region, and a short cytoplasmic tail. It associates non-covalently with beta-2-microglobulin to form a functional MHC class I molecule. The α1 and α2 domains form the peptide-binding groove that accommodates 8-10 amino acid peptides. HLA-C is unique among classical HLA class I molecules in that it has a limited polymorphism in the α3 domain, which is the primary binding site for CD8 and KIR receptors. The cytoplasmic tail contains a sorting motif that regulates endocytosis and recycling. HLA-C is expressed on nearly all nucleated cells, with highest levels on immune cells. Its expression is regulated at the transcriptional level by NF-κB and IRF1, and post-transcriptionally by microRNAs (e.g., miR-148a). The protein has a molecular weight of approximately 45 kDa (glycosylated).
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| HLA-C Knockout HEK293 Cell Line | EDJ-KQ13754 | Human | 3107 | Details Get a Quote |
| HLA-C Knockout A-549 Cell Line | EDJ-KQ43528 | Human | 3107 | Details Get a Quote |
| HLA-C Knockout HCT 116 Cell Line | EDJ-KQ43529 | Human | 3107 | Details Get a Quote |
| HLA-C Knockout HeLa Cell Line | EDJ-KQ43530 | Human | 3107 | Details Get a Quote |
| HLA-C Knockout Hep-G2 Cell Line | EDJ-KZ284 | Human | 3107 | Details Get a Quote |
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