This gene encodes the acidic 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 and type I diabetes mellitus.[6][7][8][9][10][11] Excess production due to a copy number that is higher than normal has shown a high probability of a causal relationship with schizophrenia and bipolar disorder with psychosis, which could explain the hereditary nature of these illnesses.[12] This gene localizes to the RCCX locus within the major histocompatibility complex (MHC) class III region on chromosome 6.[13][14] Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene.[5] Each copy of the gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization,[15] can be of one of two types: C4A and C4B.[16] 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.[14]
