<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">C4A Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>C4A</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Complement Component 4A (Chido/Rodgers Blood Group)</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>6p21.3 (MHC Class III)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>712</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>120810</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000144711</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P0C0P0</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Complement system serine protease</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's Disease, Parkinson's Disease, Schizophrenia, Systemic Lupus Erythematosus</td>
</tr>
<tr>
<td class="label">Cell Type</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Microglia</td>
<td>High (increases with activation)</td>
</tr>
<tr>
<td class="label">Astrocytes</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Neurons</td>
<td>Low-moderate</td>
</tr>
<tr>
<td class="label">Oligodendrocytes</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">C1q</td>
<td>Complex formation</td>
</tr>
<tr>
<td class="label">C1r</td>
<td>Protease cleavage</td>
</tr>
<tr>
<td class="label">C1s</td>
<td>Protease cleavage</td>
</tr>
<tr>
<td class="label">CR1 (CD35)</td>
<td>Receptor binding</td>
</tr>
<tr>
<td class="label">CR3 (CD11b/CD18)</td>
<td>Receptor binding</td>
</tr>
</table>
The C4A gene (Complement Component 4A) encodes a critical protein in the classical complement cascade, a key component of the innate immune system. Located in the major histocompatibility complex (MHC) class III region on chromosome 6p21.3, C4A plays essential roles in immune defense, synaptic pruning, and neuroinflammation["@sekar2016"]. Research over the past decade has revealed that C4A is critically involved in the pathogenesis of Alzheimer's disease, Parkinson's disease, schizophrenia, and other neurodegenerative conditions. The gene shows polymorphic variation in humans, including copy number variation (CNV) that has been associated with disease risk.
C4A encodes the complement component 4A protein, a 1741-amino acid zymogen that undergoes proteolytic cleavage during activation. The protein consists of three polypeptide chains (α, β, and γ) held together by disulfide bonds:
C4A participates in multiple complement activation pathways:
The cleavage products serve distinct functions:
C4A has emerged as a significant factor in Alzheimer's disease pathogenesis through multiple mechanisms:
Elevated C4A expression in the AD brain contributes to chronic neuroinflammation[@steckham2019]. Studies have shown that C4A levels are increased in AD brains compared to age-matched controls, particularly in regions affected by amyloid pathology. The complement protein is produced by activated microglia and astrocytes, creating a pro-inflammatory feedback loop that drives disease progression[@benoit2022].
Key mechanisms include:
The complement system plays a critical role in developmental synaptic pruning, and this mechanism is re-activated in Alzheimer's disease[@hong2016]. C4A contributes to:
C4A interacts with amyloid-beta (Aβ) plaques in several ways:
In Parkinson's disease, C4A contributes to dopaminergic neuron loss through:
Post-mortem studies have shown increased C4A expression in the substantia nigra of PD patients, particularly in proximity to Lewy bodies[@hawkes2023].
The strongest evidence linking C4A to disease comes from schizophrenia research:
Sekar et al. (2016) demonstrated that increased C4A copy number is associated with increased schizophrenia risk[@sekar2016]. The mechanism involves:
The schizophrenia association supports a neurodevelopmental model where:
C4A and C4B show opposing roles in multiple sclerosis[@van2020]:
C4A is expressed in multiple cell types within the central nervous system:
C4A expression varies across brain regions:
C4A expression increases with age in the brain, which may contribute to age-related neurodegeneration. This age-related increase is amplified in AD and PD brains.
The C4A gene shows extensive copy number variation:
GWAS studies have identified SNPs in the C4 region associated with:
Given the central role of C4A in neurodegeneration, complement inhibition represents a promising therapeutic strategy:
Current clinical trials are evaluating complement inhibitors in AD and other neurodegenerative conditions. The goal is to modulate neuroinflammation without compromising host defense[@presumey2022].
C4A levels in cerebrospinal fluid (CSF) may serve as:
C4A CNV analysis may help identify:
Top DisGeNET gene-disease associations for this gene are listed below. Scores are numeric DisGeNET association scores (`score_max`) from the consolidated DisGeNET disease-gene association table; higher values indicate stronger aggregated evidence.
| Disease | DisGeNET score | Evidence sources | Supporting PMID count |
|---|---:|---|---:|
| systemic lupus erythematosus | 0.243 | BeFree/CTD_human/GAD/LHGDN | 25 |
| psoriasis | 0.003 | BeFree/LHGDN | 3 |
| Graves' disease | 0.003 | BeFree/GAD | 2 |
| asthma | 0.003 | LHGDN | 1 |
| chronic obstructive pulmonary disease | 0.003 | LHGDN | 1 |
Source: DisGeNET-derived consolidated disease-gene associations (`dhimmel/disgenet`, gene symbol `C4A`).
Benoit2022, Complement protein C1q-mediated neuroprotection is reversed by chronic systemic exposure to bacterial lipopolysaccharide (2022)
chen2019, Complement C4 gene expression in microglia: therapeutic implications for Alzheimer's disease (2019)
danielsen2022, Association between complement component C4 and neurodegenerative diseases (2022)
fischer2021, Complement C3/C3aR signaling in Alzheimer's disease: new therapeutic targets (2021)
gomez2020, Microglial dynamics in Alzheimer's disease (2020)
hawkes2023, Complement activation in Alzheimer's disease: therapeutic targeting (2023)
hong2016, Complement and microglia mediate synapse elimination during development (2016)
jackson2019, Complement component C4 and the risk of Alzheimer's disease: a systematic review and meta-analysis (2019)
lambert2013, Meta-analysis of the amyloid burden in cognitively normal individuals with autosomal dominant Alzheimer's disease (2013)
lintvedt2013, C4B deficiency is associated with increased risk of Alzheimer's disease (2013) [1](https://doi.org/10.3233/JAD-121714)
morris2018, The role of complement in synaptic pruning and neurodegeneration (2018)
presumey2022, Complement system in schizophrenia: where we are and where we need to go (2022)
sarlus2022, Microglia in Alzheimer's disease (2022)
sekar2016, Schizophrenia risk from complex variation of complement component 4 (2016) [1](https://doi.org/10.1038/nature16549)
shi2020, Complement C3-deficient mice do not develop age-related retinal degeneration (2020)
steckham2019, The emerging role of complement in neurodegeneration (2019)
van2020, Opposing roles of C4A and C4B in multiple sclerosis: implications for neurodegeneration (2020)
veenvliet2020, Cross-talk between neuroinflammation and neurodegeneration in Alzheimer's disease: the role of complement C4 (2020)
wu2019, C4 in brain: implications for understanding synaptic remodeling and schizophrenia (2019) [1](https://doi.org/10.1007/s11064-019-02852-w)
zhou2020, Complement component 4 is increased in Alzheimer's disease brains (2020) [1](https://doi.org/10.1007/s12035-020-02013-1)
The following diagram shows the key molecular relationships involving C4A Gene discovered through SciDEX knowledge graph analysis: