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Gene Review

C4A  -  complement component 4A (Rodgers blood group)

Homo sapiens

Synonyms: Acidic complement C4, C3 and PZP-like alpha-2-macroglobulin domain-containing protein 2, C4, C4A2, C4A3, ...
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Disease relevance of C4A


Psychiatry related information on C4A

  • We previously reported that the complement C4B null allele appears to be associated with infantile autism [6].
  • We compared the frequency of various C4B types in 25 patients with familial Alzheimer dementia (AD), 22 patients with sporadic AD, and 360 control individuals [7].
  • We describe, for the first time, evidence for the existence of a C-4 hydroxylation pathway in the metabolism of bile acids, which may be unique to early human development [8].

High impact information on C4A

  • DNA polymorphism of the C4 genes. A new marker for analysis of the major histocompatibility complex [9].
  • C4 genomic polymorphisms are inherited with the segment of the short arm of chromosome 6 that carries the HLA-DR and complement loci [9].
  • We conclude that a DNA-protein complex involving 100 bp and terminating with the C4A4 repeat can be sufficient to provide the fundamental functions of telomeres, allowing linear DNA replication and conferring stability of linear DNA [10].
  • The short DNA molecules of the macronucleus are terminated with repeats of the octanucleotide C4A4 [11].
  • Inability to activate the classical complement pathway, abnormal kinetics of alternative-pathway activation and depressed antibody responses to a T-cell-dependent antigen may predispose C4-deficient patients to viral infection or immune-complex formation [12].

Chemical compound and disease context of C4A

  • This report deals with the genetic factors involved in insulin-dependent diabetes mellitus (IDD) in The Netherlands. Twenty-two Dutch multiplex families with IDD were typed for HLA-A, -B, -C, and -DR antigens, for BF, C2, C4, and GLO polymorphisms, as well as for GM allotypes of immunoglobulins [13].
  • Complement C4 null alleles as a marker of gold or D-penicillamine toxicity in the treatment of rheumatoid arthritis [14].
  • Liver biopsies of a 58-year-old clinically healthy patient with a hepatomegaly and intracisternal PAS-negative globular hyaline bodies were immunofluorescent-optically examined for the content of the complement components C 1 q, C 4, C 9, C 1-inactivator, C 3-activator [15].
  • Of 26 patients with autoimmune chronic active hepatitis (CAH) starting in childhood 18 (69%) had low C4 and 5 (19%) had low C3 serum levels [16].
  • Serum creatinine and proteinuria did not differ between patients with identical and C4A-dominant C4 deposition [17].

Biological context of C4A


Anatomical context of C4A

  • C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected [21].
  • By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site [22].
  • The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes [23].
  • Th inclusion bodies reacted with antisera against the complement components C 4, C 3 and C 3-activator, as also identified by double immunofluorescence [15].
  • A human hepatoma-derived cell line (HepG2), in addition to synthesizing C4s and small quantities of the polypeptide precursor of C4 (pro-C4), was found to secrete p168 and p125 at concentrations of 14 +/- 4.8 and 21 +/- 9.2% (mean +/- SD), respectively, of total secreted C4 [24].

Associations of C4A with chemical compounds

  • Extensive conservation of upstream C4 promoter sequences: a comparison between C4A and C4B [25].
  • Twelve transcriptional units have now been located in a 160 kb segment of DNA that includes the genes encoding members of the serum complement system C2, Factor B (Bf) and C4 within the class III region of the human major histocompatibility complex (MHC) [26].
  • Of the two critical events required for C5 cleavage, namely formation of a covalent adduct between C3b and the C4b subunit of the C3 convertase (C4b2a), and binding of C5 to this C4b-C3b complex, it is a defect in the latter step that accounts for the aberrant activity of C4A6 [27].
  • Previous studies have localized the defect in C4A6 to the C5 convertase stage [27].
  • The C4A and C4B isotypes of human C4 show certain functional differences that stem from their relative preference for transacylation to amino (-NH2) vs hydroxyl (-OH) nucleophiles, respectively, on complement-activating surfaces [28].

Physical interactions of C4A


Regulatory relationships of C4A


Other interactions of C4A

  • Human populations are endowed with a sophisticated genetic diversity of complement C4 and its flanking genes RP, CYP21, and TNX in the RCCX modules of the major histocompatibility complex class III region [35].
  • Characterization of a de novo conversion in human complement C4 gene producing a C4B5-like protein [36].
  • As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module [37].
  • Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families [38].
  • We did not find significant differences in Bf and C4 allotype frequencies in RA patients subdivided according to severity of the disease into a mild group and a progressive group [39].

Analytical, diagnostic and therapeutic context of C4A


  1. C4 polymorphism and major histocompatibility complex haplotypes in IgA deficiency: association with C4A null haplotypes. Bućin, D., Truedsson, L., Hammarström, L., Smith, C.I., Sjöholm, A.G. Exp. Clin. Immunogenet. (1991) [Pubmed]
  2. Rare variant of complement C4 is seen in high frequency in patients with primary glomerulonephritis. Wank, R., Schendel, D.J., O'Neill, G.J., Riethmüller, G., Held, E., Feucht, H.E. Lancet (1984) [Pubmed]
  3. HLA and complement allotypes in Type 1 (insulin-dependent) diabetes. McCluskey, J., McCann, V.J., Kay, P.H., Zilko, P.J., Christiansen, F.T., O'Neill, G.J., Dawkins, R.L. Diabetologia (1983) [Pubmed]
  4. HLA-linked complement markers in Alzheimer's and Parkinson's disease: C4 variant (C4B2) a possible marker for senile dementia of the Alzheimer type. Nerl, C., Mayeux, R., O'Neill, G.J. Neurology (1984) [Pubmed]
  5. Rapid quantification of human complement component C4A and C4B genes by capillary gel electrophoresis. Szilagyi, A., Blasko, B., Ronai, Z., Fust, G., Sasvari-Szekely, M., Guttman, A. Electrophoresis (2006) [Pubmed]
  6. Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Warren, R.P., Singh, V.K., Cole, P., Odell, J.D., Pingree, C.B., Warren, W.L., DeWitt, C.W., McCullough, M. Immunogenetics (1992) [Pubmed]
  7. The frequency of C4B variants of complement in familial and sporadic Alzheimer disease. Bird, T.D., Boehnke, M., Anderson, J., Lampe, T.H., Schellenberg, G., Larson, E.B. Alzheimer disease and associated disorders. (1987) [Pubmed]
  8. Hepatic bile acid metabolism during early development revealed from the analysis of human fetal gallbladder bile. Setchell, K.D., Dumaswala, R., Colombo, C., Ronchi, M. J. Biol. Chem. (1988) [Pubmed]
  9. DNA polymorphism of the C4 genes. A new marker for analysis of the major histocompatibility complex. Whitehead, A.S., Woods, D.E., Fleischnick, E., Chin, J.E., Yunis, E.J., Katz, A.J., Gerald, P.S., Alper, C.A., Colten, H.R. N. Engl. J. Med. (1984) [Pubmed]
  10. Chromatin structure of the molecular ends of Oxytricha macronuclear DNA: phased nucleosomes and a telomeric complex. Gottschling, D.E., Cech, T.R. Cell (1984) [Pubmed]
  11. Telomeric properties of C4A4-homologous sequences in micronuclear DNA of Oxytricha fallax. Dawson, D., Herrick, G. Cell (1984) [Pubmed]
  12. Immune response of a patient with deficiency of the fourth component of complement and systemic lupus erythematosus. Jackson, C.G., Ochs, H.D., Wedgwood, R.J. N. Engl. J. Med. (1979) [Pubmed]
  13. HLA and GM in insulin-dependent diabetes in the Netherlands: report on a combined multiplex family and population study. de Jongh, B.M., Bruining, G.J., Schreuder, G.M., Schuurman, R.K., Radder, J.K., van Loghem, E., Meera Khan, P., Hauptmann, G., van Rood, J.J. Hum. Immunol. (1984) [Pubmed]
  14. Complement C4 null alleles as a marker of gold or D-penicillamine toxicity in the treatment of rheumatoid arthritis. Clarkson, R.W., Sanders, P.A., Grennan, D.M. Br. J. Rheumatol. (1992) [Pubmed]
  15. Storage of the complement components C4, C3, and C 3-activator in the human liver as PAS-negative globular hyaline bodies. Storch, W., Riedel, H., Trautmann, B., Justus, J., Hiemann, D. Experimental pathology. (1982) [Pubmed]
  16. Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis. Vergani, D., Wells, L., Larcher, V.F., Nasaruddin, B.A., Davies, E.T., Mieli-Vergani, G., Mowat, A.P. Lancet (1985) [Pubmed]
  17. Glomerular deposition of the complement C4 isotypes C4A and C4B in glomeruonephritis. Lhotta, K., Schlogl, A., Kronenberg, F., Joannidis, M., Konig, P. Nephrol. Dial. Transplant. (1996) [Pubmed]
  18. Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man. Awdeh, Z.L., Raum, D., Yunis, E.J., Alper, C.A. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  19. Correlation between a DNA restriction fragment length polymorphism and C4A6 protein. Palsdottir, A., Cross, S.J., Edwards, J.H., Carroll, M.C. Nature (1983) [Pubmed]
  20. Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus. Braun, L., Schneider, P.M., Giles, C.M., Bertrams, J., Rittner, C. J. Exp. Med. (1990) [Pubmed]
  21. Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes. Lokki, M.L., Circolo, A., Ahokas, P., Rupert, K.L., Yu, C.Y., Colten, H.R. J. Immunol. (1999) [Pubmed]
  22. DNase I hypersensitivity mapping and promoter polymorphism analysis of human C4. Vaishnaw, A.K., Hargreaves, R., Campbell, R.D., Morley, B.J., Walport, M.J. Immunogenetics (1995) [Pubmed]
  23. Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4. Blanchong, C.A., Chung, E.K., Rupert, K.L., Yang, Y., Yang, Z., Zhou, B., Moulds, J.M., Yu, C.Y. Int. Immunopharmacol. (2001) [Pubmed]
  24. Identification and structural characterization of two incompletely processed forms of the fourth component of human complement. Chan, A.C., Atkinson, J.P. J. Clin. Invest. (1983) [Pubmed]
  25. Extensive conservation of upstream C4 promoter sequences: a comparison between C4A and C4B. Ulgiati, D., Abraham, L.J. Tissue Antigens (1996) [Pubmed]
  26. Characterisation of the novel gene G11 lying adjacent to the complement C4A gene in the human major histocompatibility complex. Sargent, C.A., Anderson, M.J., Hsieh, S.L., Kendall, E., Gomez-Escobar, N., Campbell, R.D. Hum. Mol. Genet. (1994) [Pubmed]
  27. A single arginine to tryptophan interchange at beta-chain residue 458 of human complement component C4 accounts for the defect in classical pathway C5 convertase activity of allotype C4A6. Implications for the location of a C5 binding site in C4. Ebanks, R.O., Jaikaran, A.S., Carroll, M.C., Anderson, M.J., Campbell, R.D., Isenman, D.E. J. Immunol. (1992) [Pubmed]
  28. Amino acid residues 1101-1105 of the isotypic region of human C4B is important to the covalent binding activity of complement component C4. Reilly, B.D., Levine, R.P., Skanes, V.M. J. Immunol. (1991) [Pubmed]
  29. Fourth component of Xenopus laevis complement: cDNA cloning and linkage analysis of the frog MHC. Mo, R., Kato, Y., Nonaka, M., Nakayama, K., Takahashi, M. Immunogenetics (1996) [Pubmed]
  30. Two isotypes of human C4, C4A and C4B have different structure and function. Schifferli, J.A., Paccaud, J.P. Complement and inflammation. (1989) [Pubmed]
  31. Aggregation of LDL with chondroitin-4-sulfate makes LDL oxidizable in the presence of water-soluble antioxidants. Abuja, P.M. FEBS Lett. (2002) [Pubmed]
  32. C4-mediated inhibition of immune precipitation and differences in inhibitory action of genetic variants, C4A3 and C4B1. Paul, L., Skanes, V.M., Mayden, J., Levine, R.P. Complement (1988) [Pubmed]
  33. Counterregulatory effects of interferon-gamma and endotoxin on expression of the human C4 genes. Kulics, J., Colten, H.R., Perlmutter, D.H. J. Clin. Invest. (1990) [Pubmed]
  34. Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus. Speirs, C., Fielder, A.H., Chapel, H., Davey, N.J., Batchelor, J.R. Lancet (1989) [Pubmed]
  35. Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. Chung, E.K., Yang, Y., Rennebohm, R.M., Lokki, M.L., Higgins, G.C., Jones, K.N., Zhou, B., Blanchong, C.A., Yu, C.Y. Am. J. Hum. Genet. (2002) [Pubmed]
  36. Characterization of a de novo conversion in human complement C4 gene producing a C4B5-like protein. Jaatinen, T., Eholuoto, M., Laitinen, T., Lokki, M.L. J. Immunol. (2002) [Pubmed]
  37. Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. Yang, Z., Mendoza, A.R., Welch, T.R., Zipf, W.B., Yu, C.Y. J. Biol. Chem. (1999) [Pubmed]
  38. Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families. Sinnott, P.J., Costigan, C., Dyer, P.A., Harris, R., Strachan, T. Hum. Genet. (1991) [Pubmed]
  39. Properdin factor B and complement factor C4 allotypes in rheumatoid arthritis: results of a follow-up study. van Zeben, D., Giphart, M.J., Christiansen, F.T., Hoetjer, M., Meyer, E.C., Breedveld, F.C. Hum. Immunol. (1992) [Pubmed]
  40. Polymorphism of complement C4 and susceptibility to IDDM and microvascular complications. Lhotta, K., Auinger, M., Kronenberg, F., Irsigler, K., König, P. Diabetes Care (1996) [Pubmed]
  41. Human C4 polymorphism: pedigree analysis of qualitative, quantitative, and functional parameters as a basis for phenotype interpretations. Mauff, G., Bender, K., Giles, C.M., Goldmann, S., Opferkuch, W., Wachauf, B. Hum. Genet. (1984) [Pubmed]
  42. Evidence for development of capillary leak syndrome associated with cardiopulmonary bypass in pediatric patients with the homozygous C4A null phenotype. Zhang, S., Wang, S., Yao, S. Anesthesiology (2004) [Pubmed]
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