Complement component 4
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.
[2] 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.
[4] Moreover, the two loci are linked to the HLA, or the human analog of the major histocompatibility complex (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.
[6] 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.
[7] The C4 protein consists of 3 subunits (α, β, and γ) having molecular weights (MWs) of ~95,000, 78,000, and 31,000, respectively and they are all joined by interchain disulfide bridges.
[7] 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.
[11] 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.
[10][11] In the same year, studies relatedly identified a 98 kb region of the chromosome the four class III genes (that express C4A, C4B, C2, and factor B) are closely linked, which does not allow for cross-overs to occur.
[10] In another study, Law et al. then continued to delve deeper, this time comparing the properties of both the C4A and C4B, both of which are substantial players in the human immunity system.
[12] Thus, upon analysis of the varying reactivities, they proposed that the exceptional polymorphism of C4 genes may bring about some biological advantages (i.e. complement activation with a more extensive range of Ab-Ag complexes formed upon infections).
[citation needed] The early studies vastly expanded the knowledge of the C4 complex, laying down the foundations that paved the way to discovering the gene and protein structures.
[13] Their research concluded with the fact that the Sp1 binding site (positioned at -59 to -49) plays an important role in accurately starting basal transcription of C4.
[13] Utilization of electromobility shift assays and DNase I footprint analyses demonstrated specific DNA-protein correlations of the C4 promoter at the nuclear factor 1, two E box (-98 to -93 and -78 to -73), and Sp1 binding domains.
In the Wu et al. study, they utilized the real-time polymerase chain reaction (rt-PCR) as an assay to determine the copy number variance (CNV) or genetic diversity of C4.
[20] CNVs (and associated polymorphisms) play a role in filling in the gap towards understanding the genetic basis of quantitative traits and the different susceptibilities to autoimmune and neurobiological diseases.
[citation needed] Substantial data from all over the world has been collected and analyzed to determine that schizophrenia, indeed, has a strong genetic relationship with a region in the MHC locus on chromosome arm 6.
[1] They found out two features: 1) A great number of SNPs reaching only 2Mb across the end, 2) peak of association centered at C4, predicting that C4A expression levels is most strongly correlated with schizophrenia.
