C4A explained

Complement C4-A is a kind of the Complement component 4 protein that in humans is encoded by the C4A gene.^[1]

Function

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]} 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.^[8] This gene localizes to the RCCX locus within the major histocompatibility complex (MHC) class III region on chromosome 6.^{[9] [10]} Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. Each copy of the gene, due to five adjacent nucleotide substitutions cause four amino acid changes and immunological subfunctionalization,^[11] can be of one of two types: C4A and C4B.^[12] 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.^[10]

See also

• Complement component 4
  • Complement component 4B
• HLA A1-B8-DR3-DQ2 haplotype
• Complement system
• Complement deficiency

Further reading

• Hugli TE . Biochemistry and biology of anaphylatoxins . Complement . 3 . 3 . 111–27 . 1987 . 3542363 . 10.1159/000467889.
• Yu CY . Molecular genetics of the human MHC complement gene cluster . Experimental and Clinical Immunogenetics . 15 . 4 . 213–30 . 1999 . 10072631 . 10.1159/000019075 . 25061446 .
• Anderson MJ, Milner CM, Cotton RG, Campbell RD . 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 . May 1992 . 10.4049/jimmunol.148.9.2795 . 1573268 . 9549384 . free .
• Hessing M, van 't Veer C, Hackeng TM, Bouma BN, Iwanaga S . Importance of the alpha 3-fragment of complement C4 for the binding with C4b-binding protein . FEBS Letters . 271 . 1–2 . 131–6 . Oct 1990 . 1699796 . 10.1016/0014-5793(90)80389-Z . 84173713 . free .
• Yu CY . 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 . Feb 1991 . 10.4049/jimmunol.146.3.1057 . 1988494 . 10028332 . free .
• Ghiso J, Saball E, Leoni J, Rostagno A, Frangione B . Binding of cystatin C to C4: the importance of sense-antisense peptides in their interaction . Proceedings of the National Academy of Sciences of the United States of America . 87 . 4 . 1288–91 . Feb 1990 . 2304899 . 53459 . 10.1073/pnas.87.4.1288 . 1990PNAS...87.1288G . free .
• Yu CY, Belt KT, Giles CM, Campbell RD, Porter RR . Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity . The EMBO Journal . 5 . 11 . 2873–81 . Nov 1986 . 2431902 . 1167237 . 10.1002/j.1460-2075.1986.tb04582.x.
• Speiser PW, White PC . 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 . Dec 1989 . 2612324 . 10.1089/dna.1989.8.745 .
• Palsdottir A, Fossdal R, Arnason A, Edwards JH, Jensson O . 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 . 1987 . 2883116 . 10.1007/BF00404422 . 38417056 .
• Kishore N, Shah D, Skanes VM, Levine RP . The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins . Molecular Immunology . 25 . 9 . 811–9 . Sep 1988 . 3264881 . 10.1016/0161-5890(88)90117-4 .
• Chakravarti DN, Campbell RD, Porter RR . The chemical structure of the C4d fragment of the human complement component C4 . Molecular Immunology . 24 . 11 . 1187–97 . Nov 1987 . 3696167 . 10.1016/0161-5890(87)90165-9 .
• Belt KT, Yu CY, Carroll MC, Porter RR . Polymorphism of human complement component C4 . Immunogenetics . 21 . 2 . 173–80 . 1985 . 3838531 . 10.1007/BF00364869 . 40614897 .
• Hortin G, Sims H, Strauss AW . Identification of the site of sulfation of the fourth component of human complement . The Journal of Biological Chemistry . 261 . 4 . 1786–93 . Feb 1986 . 10.1016/S0021-9258(17)36009-X . 3944109 . free .
• Moon KE, Gorski JP, Hugli TE . Complete primary structure of human C4a anaphylatoxin . The Journal of Biological Chemistry . 256 . 16 . 8685–92 . Aug 1981 . 10.1016/S0021-9258(19)68898-8 . 6167582 . free .
• Palsdottir A, Cross SJ, Edwards JH, Carroll MC . Correlation between a DNA restriction fragment length polymorphism and C4A6 protein . Nature . 306 . 5943 . 615–6 . 1984 . 6316164 . 10.1038/306615a0 . 4347111 .
• Belt KT, Carroll MC, Porter RR . The structural basis of the multiple forms of human complement component C4 . Cell . 36 . 4 . 907–14 . Apr 1984 . 6546707 . 10.1016/0092-8674(84)90040-0 . 38655580 .
• Carroll MC, Campbell RD, Bentley DR, Porter RR . 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 . 1984 . 6559257 . 10.1038/307237a0 . 1984Natur.307..237C . 12016613 .
• Carroll MC, Porter RR . Cloning of a human complement component C4 gene . Proceedings of the National Academy of Sciences of the United States of America . 80 . 1 . 264–7 . Jan 1983 . 6572000 . 393353 . 10.1073/pnas.80.1.264 . 1983PNAS...80..264C . free .
• Whitehead AS, Goldberger G, Woods DE, Markham AF, Colten HR . Use of a cDNA clone for the fourth component of human complement (C4) for analysis of a genetic deficiency of C4 in guinea pig . Proceedings of the National Academy of Sciences of the United States of America . 80 . 17 . 5387–91 . Sep 1983 . 6577433 . 384261 . 10.1073/pnas.80.17.5387 . 1983PNAS...80.5387W . free .

Notes and References

1. Web site: Entrez Gene: C4A complement component 4A (Rodgers blood group).
2. Dawkins RL, Uko G, Christiansen FT, Kay PH . Low C4 concentrations in insulin dependent diabetes mellitus . British Medical Journal . 287 . 6395 . 839 . Sep 1983 . 6412852 . 1549128 . 10.1136/bmj.287.6395.839-b .
3. Vergani D, Johnston C, B-Abdullah N, Barnett AH . Low serum C4 concentrations: an inherited predisposition to insulin dependent diabetes? . British Medical Journal . 286 . 6369 . 926–8 . Mar 1983 . 6403137 . 1547358 . 10.1136/bmj.286.6369.926 .
4. Mijovic CH, Fletcher JA, Bradwell AR, Barnett AH . Low C4 levels in type 1 (insulin-dependent) diabetes . Diabetologia . 30 . 10 . 824 . Oct 1987 . 3428499 . 10.1007/bf00275752 . free .
5. Thomsen M, Mølvig J, Zerbib A, de Preval C, Abbal M, Dugoujon JM, Ohayon E, Svejgaard A, Cambon-Thomsen A, Nerup J . 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 . 1988 . 3139557 . 10.1007/BF00364230 . 6521141 .
6. Jenhani F, Bardi R, Gorgi Y, Ayed K, Jeddi M . 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 . Apr 1992 . 1352685 . 10.1016/0896-8411(92)90196-w .
7. Lhotta K, Auinger M, Kronenberg F, Irsigler K, König P. Polymorphism of complement C4 and susceptibility to IDDM and microvascular complications. Diabetes Care. 1996. 19. 1. 53–55. 10.2337/diacare.19.1.53. 8720534. 8999525.
8. Melbourne JK, Rosen C, Feiner B, Sharma RP . C4A mRNA expression in PBMCs predicts the presence and severity of delusions in schizophrenia and bipolar disorder with psychosis . Schizophrenia Research . 197 . 321–327 . July 2018 . 29449061 . 6087677 . 10.1016/j.schres.2018.01.018 .
9. Zhou D, Rudnicki M, Chua GT, Lawrance SK, Zhou B, Drew JL, Barbar-Smiley F, Armstrong TK, Hilt ME, Birmingham DJ, Passler W, Auletta JJ, Bowden SA, Hoffman RP, Wu YL, Jarjour WN, Mok CC, Ardoin SP, Lau YL, Yu CY . Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases . Front Immunol . 12 . 739430 . 2021 . 34764957 . 8577214 . 10.3389/fimmu.2021.739430 . free .
10. Carrozza C, Foca L, De Paolis E, Concolino P . Genes and Pseudogenes: Complexity of the RCCX Locus and Disease . Front Endocrinol (Lausanne) . 12 . 709758 . 2021 . 34394006 . 8362596 . 10.3389/fendo.2021.709758 . free .
11. Bánlaki Z, Szabó JA, Szilágyi Á, Patócs A, Prohászka Z, Füst G, Doleschall M . Intraspecific evolution of human RCCX copy number variation traced by haplotypes of the CYP21A2 gene . Genome Biol Evol . 5 . 1 . 98–112 . 2013 . 23241443 . 3595039 . 10.1093/gbe/evs121 .
12. Doleschall M, Luczay A, Koncz K, Hadzsiev K, Erhardt É, Szilágyi Á, Doleschall Z, Németh K, Török D, Prohászka Z, Gereben B, Fekete G, Gláz E, Igaz P, Korbonits M, Tóth M, Rácz K, Patócs A . A unique haplotype of RCCX copy number variation: from the clinics of congenital adrenal hyperplasia to evolutionary genetics . Eur J Hum Genet . 25 . 6 . 702–710 . June 2017 . 28401898 . 5477366 . 10.1038/ejhg.2017.38 .