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.[2][3][4][5][6][7] This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene.[1]
↑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.
↑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&ndash, 55. doi:10.2337/diacare.19.1.53.
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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.
Hessing M, van 't Veer C, Hackeng TM, Bouma BN, Iwanaga S (Oct 1990). "Importance of the alpha 3-fragment of complement C4 for the binding with C4b-binding protein". FEBS Letters. 271 (1–2): 131–6. doi:10.1016/0014-5793(90)80389-Z. PMID1699796.
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.
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.
Belt KT, Yu CY, Carroll MC, Porter RR (1985). "Polymorphism of human complement component C4". Immunogenetics. 21 (2): 173–80. doi:10.1007/BF00364869. PMID3838531.
Hortin G, Sims H, Strauss AW (Feb 1986). "Identification of the site of sulfation of the fourth component of human complement". The Journal of Biological Chemistry. 261 (4): 1786–93. PMID3944109.
Moon KE, Gorski JP, Hugli TE (Aug 1981). "Complete primary structure of human C4a anaphylatoxin". The Journal of Biological Chemistry. 256 (16): 8685–92. PMID6167582.
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.
Belt KT, Carroll MC, Porter RR (Apr 1984). "The structural basis of the multiple forms of human complement component C4". Cell. 36 (4): 907–14. doi:10.1016/0092-8674(84)90040-0. PMID6546707.
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. doi:10.1038/307237a0. PMID6559257.
