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Chemical Compound Review

AC1O4WLM     ethylN-[(2S)-6-amino-1-[5- [[4-(2,3...

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Disease relevance of C4A

  • Guinea pigs deficient in C4 were reconstituted transiently with either human C4A or C4B protein and immunized with the bacteriophage phi X174 [1].
  • The combined data suggest that C4A null alleles predispose strongly to development of lupus, whereas the influence of hv3005 deletion is relatively weak [2].
  • Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH) [3].
  • Expression of C4A and C4B genes is regulated by IFN-gamma in human hepatoma cells and in murine fibroblasts transformed with the respective genes [4].
  • METHODS: Twenty-four white patients with autoimmune hepatitis were studied by Southern blots using a C4A gene complementary DNA probe [5].

Psychiatry related information on C4A

  • CONCLUSION: These results suggest that C4A treatment may reduce the risk of developing Alzheimer's dementia in elderly women [6].

High impact information on C4A

  • The fourth component of complement (C4) in man, is coded for by two separate but closely linked loci (C4A and C4B) within the major histocompatibility region (MHC), on the short arm of chromosome 6 [7].
  • An animal model has been used to address the question of the biological importance of the known structural difference between the two isotypes of human C4, i.e., C4A and C4B [1].
  • All nondeleted AQ0 allels had C4A-specific sequences and may thus be described as pseudogenes, whereas the nondeleted BQ0 alleles had C4A-instead of C4B-specific sequences [8].
  • Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus [8].
  • The results show a strong association between C4A deletion and SLE in these families [2].

Chemical compound and disease context of C4A

  • Twelve of 19 patients with common variable immunodeficiency (63%, P less than 0.001) and 9 of 16 patients with IgA deficiency (56%, P less than 0.01) had rare C2 alleles and/or C4A and 21-hydroxylase A deletions, whereas these gene features were seen in only 5 of 34 healthy individuals (15%) in the control group [9].
  • Phenotype frequencies for the complement proteins C4A, C4B, Bf (factor B) and C3 were performed for 49 Caucasian patients with psoriasis [10].

Biological context of C4A

  • Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6% [11].
  • Gene conversion is the probable mechanism by which a C4A gene is found at the second C4 locus normally occupied by C4B genes [8].
  • We studied this region of the MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB [3].
  • Moreover, no correlation is detected between the occurrence of hv3005 deletion and C4A null alleles in lupus patients, suggesting that the effects of these genetic polymorphisms on predisposition to lupus are independent [2].
  • Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to nonexpression [12].

Anatomical context of C4A

  • In these cell lines, IFN-gamma has a significantly greater and longer-lasting effect on expression of C4A than that of C4B [4].
  • In a previous study we demonstrated that the thioester-mediated transacylation of the human C4B isotype onto sheep erythrocytes (ES) was approximately fourfold more efficient than that of C4A [13].
  • Furthermore, with human erythrocytes and two human leukocyte cell lines, K562 and U937, the C4B to C4A deposition ratio decreased from greater than 4 with ES to between 1.5 and 2 [13].
  • These results show that the PIP defect cannot be explained by low levels of C4A alone and suggest that measurements of anti-C1q antibodies may be useful in future studies on the molecular cause of the PIP defect in autoimmune connective tissue disease [14].
  • In preparation for a bone marrow transplantation 217 patients and their families were complotyped for Bf, C4A and C4B in addition to the routinely performed HLA-A,B,C,DR and HLA-D typing [15].

Associations of C4A with other chemical compounds

  • This proposal was supported by our finding that individuals with these immunodeficiencies have in common a high incidence of C4A gene deletions and C2 rare gene alleles [16].
  • 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 [17].
  • Hydralazine binds covalently to complement component C4. Different reactivity of C4A and C4B gene products [18].
  • METHODS: Using electrophoresis and immunofixation techniques, we determined the allele frequencies of C4A, C4B, C3, and factor B in 42 patients with a history of HG [19].
  • All of 22 SLE patients, and 12 of 15 normal subjects who had C4A and CYP21A gene deletions had a 10.0kb Taq 1 DRB RFLP attributable to the presence of HLA-DR3 [20].

Gene context of C4A

  • Nine of 11 patients with C4A deletion had an HLA haplotype consistent with the MHC supratype HLA-A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3 previously found to be associated with IgA deficiency [9].
  • Eight combinations of HLA-B, DR, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected [21].
  • In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA-A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families [22].
  • Two steroid 21-hydroxylase genes are normally present within the human major histocompatibility complex near the genes encoding the fourth component of complement (C4A and C4B) [23].
  • This gene and a highly homologous pseudogene, CYP21A, alternate with the C4A and C4B genes encoding the fourth component of complement [24].

Analytical, diagnostic and therapeutic context of C4A

  • To further characterize the molecular basis of these non-expressed C4A genes, we selected nine pairs of PCR primers from flanking genomic intron sequences to amplify all 41 exons from individuals with a defective C4A gene [12].
  • As detected by Southern blot analysis, the C4A gene was deleted from both chromosomes in 8 of the 9 C4A-null patients [25].
  • Immunofixation, genomic restriction fragment length polymorphisms, and pulsed field gel electrophoresis experiments revealed the presence of monomodular RP-C4-CYP21-TNX (RCCX) modules, each containing a solitary, long C4A mutant gene [26].
  • Interestingly, SDS-PAGE profiles of radiolabeled C4A and C4B, which had been covalently deposited on the various cells, suggested a further degree of transacylation specificity, as the two isotypic alpha-chains sometimes bound to different membrane components [13].
  • These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis [27].


  1. Structural differences between the two human complement C4 isotypes affect the humoral immune response. Finco, O., Li, S., Cuccia, M., Rosen, F.S., Carroll, M.C. J. Exp. Med. (1992) [Pubmed]
  2. Population and family studies of three disease-related polymorphic genes in systemic lupus erythematosus. Huang, D.F., Siminovitch, K.A., Liu, X.Y., Olee, T., Olsen, N.J., Berry, C., Carson, D.A., Chen, P.P. J. Clin. Invest. (1995) [Pubmed]
  3. Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants. Schneider, P.M., Carroll, M.C., Alper, C.A., Rittner, C., Whitehead, A.S., Yunis, E.J., Colten, H.R. J. Clin. Invest. (1986) [Pubmed]
  4. 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]
  5. Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Scully, L.J., Toze, C., Sengar, D.P., Goldstein, R. Gastroenterology (1993) [Pubmed]
  6. Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. Andrieu, S., Gillette, S., Amouyal, K., Nourhashemi, F., Reynish, E., Ousset, P.J., Albarede, J.L., Vellas, B., Grandjean, H. J. Gerontol. A Biol. Sci. Med. Sci. (2003) [Pubmed]
  7. 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]
  8. 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]
  9. Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Schaffer, F.M., Palermos, J., Zhu, Z.B., Barger, B.O., Cooper, M.D., Volanakis, J.E. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  10. Complement phenotypes in patients with psoriasis. Wyatt, R.J., Wang, C., Hudson, E.C., Jones, R.M., Noah, P.W., Rosenberg, E.W. Hum. Hered. (1989) [Pubmed]
  11. Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. Blanchong, C.A., Zhou, B., Rupert, K.L., Chung, E.K., Jones, K.N., Sotos, J.F., Zipf, W.B., Rennebohm, R.M., Yung Yu, C. J. Exp. Med. (2000) [Pubmed]
  12. Genetic basis of human complement C4A deficiency. Detection of a point mutation leading to nonexpression. Barba, G., Rittner, C., Schneider, P.M. J. Clin. Invest. (1993) [Pubmed]
  13. Covalent binding properties of the C4A and C4B isotypes of the fourth component of human complement on several C1-bearing cell surfaces. Isenman, D.E., Young, J.R. J. Immunol. (1986) [Pubmed]
  14. Defective prevention of immune precipitation in autoimmune diseases is independent of C4A*Q0. Arason, G.J., Kolka, R., Hreidarsson, A.B., Gudjonsson, H., Schneider, P.M., Fry, L., Arnason, A. Clin. Exp. Immunol. (2005) [Pubmed]
  15. Relevance of complotyping and subtyping of MHC class I gene products in haplotype definition for allogeneic bone marrow transplantation. Doxiadis, G., Doxiadis, I., Frenz, G., Vögeler, U., Grosse-Wilde, H. Bone Marrow Transplant. (1989) [Pubmed]
  16. Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. Volanakis, J.E., Zhu, Z.B., Schaffer, F.M., Macon, K.J., Palermos, J., Barger, B.O., Go, R., Campbell, R.D., Schroeder, H.W., Cooper, M.D. J. Clin. Invest. (1992) [Pubmed]
  17. 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]
  18. Hydralazine binds covalently to complement component C4. Different reactivity of C4A and C4B gene products. Sim, E., Law, S.K. FEBS Lett. (1985) [Pubmed]
  19. Complement polymorphism in herpes gestationis: association with C4 null allele. Shornick, J.K., Artlett, C.M., Jenkins, R.E., Briggs, D.C., Welsh, K.I., Garvey, M.P., Kelly, S.E., Black, M.M. J. Am. Acad. Dermatol. (1993) [Pubmed]
  20. DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus. So, A.K., Fielder, A.H., Warner, C.A., Isenberg, D.A., Batchelor, J.R., Walport, M.J. Tissue Antigens (1990) [Pubmed]
  21. 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]
  22. The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus. Schur, P.H., Marcus-Bagley, D., Awdeh, Z., Yunis, E.J., Alper, C.A. Arthritis Rheum. (1990) [Pubmed]
  23. Family studies of the steroid 21-hydroxylase and complement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands. Koppens, P.F., Hoogenboezem, T., Halley, D.J., Barendse, C.A., Oostenbrink, A.J., Degenhart, H.J. Eur. J. Pediatr. (1992) [Pubmed]
  24. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. White, P.C., Vitek, A., Dupont, B., New, M.I. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  25. Deletion of C4A genes in patients with systemic lupus erythematosus. Kemp, M.E., Atkinson, J.P., Skanes, V.M., Levine, R.P., Chaplin, D.D. Arthritis Rheum. (1987) [Pubmed]
  26. Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus. Yang, Y., Lhotta, K., Chung, E.K., Eder, P., Neumair, F., Yu, C.Y. J. Immunol. (2004) [Pubmed]
  27. 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]
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