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]
^Thomsen M, Mølvig J, Zerbib A, de Preval C, Abbal M, Dugoujon JM, Ohayon E, Svejgaard A, Cambon-Thomsen A, Nerup J (1988). "The susceptibility to insulin-dependent diabetes mellitus is associated with C4 allotypes independently of the association with HLA-DQ alleles in HLA-DR3,4 heterozygotes". Immunogenetics. 28 (5): 320–7. doi:10.1007/BF00364230. PMID3139557. S2CID6521141.
^Jenhani F, Bardi R, Gorgi Y, Ayed K, Jeddi M (Apr 1992). "C4 polymorphism in multiplex families with insulin dependent diabetes in the Tunisian population: standard C4 typing methods and RFLP analysis". Journal of Autoimmunity. 5 (2): 149–60. doi:10.1016/0896-8411(92)90196-w. PMID1352685.
^Lhotta K, Auinger M, Kronenberg F, Irsigler K, König P (1996). "Polymorphism of complement C4 and susceptibility to IDDM and microvascular complications". Diabetes Care. 19 (1): 53–55. doi:10.2337/diacare.19.1.53. PMID8720534. S2CID8999525.
Hugli TE (1987). "Biochemistry and biology of anaphylatoxins". Complement. 3 (3): 111–27. doi:10.1159/000467889. PMID3542363.
Yu CY (1999). "Molecular genetics of the human MHC complement gene cluster". Experimental and Clinical Immunogenetics. 15 (4): 213–30. doi:10.1159/000019075. PMID10072631. S2CID25061446.
Anderson MJ, Milner CM, Cotton RG, Campbell RD (May 1992). "The coding sequence of the hemolytically inactive C4A6 allotype of human complement component C4 reveals that a single arginine to tryptophan substitution at beta-chain residue 458 is the likely cause of the defect". Journal of Immunology. 148 (9): 2795–802. PMID1573268.
Yu CY (Feb 1991). "The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene". Journal of Immunology. 146 (3): 1057–66. PMID1988494.
Speiser PW, White PC (Dec 1989). "Structure of the human RD gene: a highly conserved gene in the class III region of the major histocompatibility complex". DNA. 8 (10): 745–51. doi:10.1089/dna.1989.8.745. PMID2612324.
Palsdottir A, Fossdal R, Arnason A, Edwards JH, Jensson O (1987). "Heterogeneity of human C4 gene size. A large intron (6.5 kb) is present in all C4A genes and some C4B genes". Immunogenetics. 25 (5): 299–304. doi:10.1007/BF00404422. PMID2883116. S2CID38417056.
Kishore N, Shah D, Skanes VM, Levine RP (Sep 1988). "The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins". Molecular Immunology. 25 (9): 811–9. doi:10.1016/0161-5890(88)90117-4. PMID3264881.
Chakravarti DN, Campbell RD, Porter RR (Nov 1987). "The chemical structure of the C4d fragment of the human complement component C4". Molecular Immunology. 24 (11): 1187–97. doi:10.1016/0161-5890(87)90165-9. PMID3696167.
Palsdottir A, Cross SJ, Edwards JH, Carroll MC (1984). "Correlation between a DNA restriction fragment length polymorphism and C4A6 protein". Nature. 306 (5943): 615–6. doi:10.1038/306615a0. PMID6316164. S2CID4347111.
Carroll MC, Campbell RD, Bentley DR, Porter RR (1984). "A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B". Nature. 307 (5948): 237–41. Bibcode:1984Natur.307..237C. doi:10.1038/307237a0. PMID6559257. S2CID12016613.
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