This gene encodes the basic form of complement factor 4, part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus. This gene localizes to the RCCX locus within the major histocompatibility complex (MHC) class III region on chromosome 6.[6][7] Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. In addition, this gene exists as a long form and a short form due to the presence or absence of a 6.4 kb endogenous HERV-K retrovirus in intron 9. [provided by RefSeq, Jul 2008].[5] Each copy of the gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization,[8] can be of one of two types: C4A and C4B.[9] Each gene contains 41 exons and has a dichotomous size variation between approximately 22 kb and 16 kb, with the longer variant being the result of the integration of the endogenous retrovirus HERV-K(C4) into intron 9.[7]
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Teisberg P, Akesson I, Olaisen B, Gedde-Dahl T, Thorsby E (Nov 1976). "Genetic polymorphism of C4 in man and localisation of a structural C4 locus to the HLA gene complex of chromosome 6". Nature. 264 (5583): 253–4. Bibcode:1976Natur.264..253T. doi:10.1038/264253a0. PMID1088823. S2CID4241132.
Kramer J, Harcos P, Prohászka Z, Horváth L, Karádi I, Singh M, Császár A, Romics L, Füst G (Nov 2000). "Frequencies of certain complement protein alleles and serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases". Stroke: A Journal of Cerebral Circulation. 31 (11): 2648–52. doi:10.1161/01.STR.31.11.2648. PMID11062289. S2CID14128121.
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