Complement component 4
| complement component 4A (Rodgers blood group) | |
|---|---|
| Identifiers | |
| Symbol | C4A |
| Entrez | 720 |
| HUGO | 1323 |
| OMIM | 120810 |
| RefSeq | NM_007293 |
| UniProt | P0C0L4 |
| Other data | |
| Locus | Chr. 6 p21.3 |
| complement component 4B (Chido blood group) |
|
|---|---|
| Identifiers | |
| Symbol | C4B |
| Entrez | 721 |
| HUGO | 1324 |
| OMIM | 120820 |
| RefSeq | NM_000592 |
| UniProt | P0C0L5 |
| Other data | |
| Locus | Chr. 6 p21.3 |
Complement component 4 (C4), in humans, is a protein involved in the intricate complement system, originating from the human leukocyte antigen (HLA) system. It serves a number of critical functions in immunity, tolerance, and autoimmunity with the other numerous components. Furthermore, it is a crucial factor in connecting the recognition pathways of the overall system instigated by antibody-antigen (Ab-Ag) complexes to the other effector proteins of the innate immune response. For example, the severity of a dysfunctional complement system can lead to fatal diseases and infections. Complex variations of it can also lead to schizophrenia. Yet, the C4 protein derives from a simple two-locus allelic model, the C4A-C4B genes, that allows for an abundant variation in the levels of their respective proteins within a population. Originally defined in the context of the Chido/Rodgers blood group system, the C4A-C4B genetic model is under investigation for its possible role in schizophrenia risk and development.
One of the earlier genetic studies on the C4 protein identified two different groups, found within a human serum, called the Chido/Rogers (Ch/Rg) blood groups. O’Neill et al. have demonstrated that two different C4 loci express the different Ch/Rg antigens on the membranes of erythrocytes. More specifically, the two proteins, Ch and Rg, function together as a medium for interaction between the Ab-Ag complex and other complement components. Moreover, the two loci are linked to the HLA, or the human analog of the (MHC) on the short arm of chromosome 6, whereas previously they were believed to have been expressed by two codominant alleles at a single locus. In gel electrophoresis studies, O’Neill et al. have identified two genetic variants: F, signifying the presence (F+) or absence (f0/ f0) of four fast moving bands, and S, signifying the presence (S+) or absence (s0/ s0) of four slow moving bands. The homogeneity or heterogeneity of the two loci, with the addition of these null (f0, s0) genes, allow for duplication/non-duplication of the C4 loci. Therefore, having separate loci for C4, C4F and C4S (later identified as C4A or C4B, respectively), possibly account for producing multiple allelic forms, leading to the great size and copy number variation.
Two important contributors, Carroll and Porter, in their study of cloning the human C4 gene, which consists of 3 subparts (α, β, and γ subunits), showed that all six of their clones contained the same C4 gene. Regarding the subunits, the α-, β-, and γ-chains were before found to have molecular weights (MWs) of ~95,000, 78,000, and 31,000, respectively, all joined by interchain disulfide bridges. In a study by Roos et al., the α-chains between the C4A and C4B were found to be slightly different (MW of ~96,000 and 94,000, respectively), proving that there is actually a structural difference between the two variants. Moreover, they implicated that a lack of C4 activity could be attributed to the structural differences between the α-chains. Nevertheless, Carroll and Porter demonstrated that there is a 1,500-bp region that acts as an intron in the genomic sequence, which they believed to be the known C4d region, a byproduct of C4 activity. Carroll et al. later published work that characterized the structure and organization of the C4 genes, which are situated in the HLA class III region and linked with C2 and factor B on the chromosome. Through experiments involving restriction mapping, nucleotide sequence analysis, and hybridization with C4A and C4B, they found that the genes are actually fairly similar though they have their differences. For example, single nucleotide polymorphisms were detected, which allowed them to be class differences between C4A and C4B. Furthermore, class and allelic differences would affect the performance of the C4 proteins with the immune complex. Finally, by overlapping cDNA cloned fragments, they were able to determine that the C4 loci, an estimated 16 kilobase (kb) long, are spaced by 10 kb and aligned 30 kb from the factor B locus.
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