Skip to main content
SpringerLink
Log in

Human C4 polymorphism: Pedigree analysis of qualitative, quantiative, and functional parameters as a basis for phenotype interpretations

  • Original Investigations
  • Published:
Human Genetics Aims and scope Submit manuscript

Summary

Ten families with 82 members were investigated for C4A- and B polymorphism in a blind trial. Phenotyping was done on neuraminidase treated sera by immunofixation and simulataneously by hemolytic overlay electrophoresis. In addition Rg, Ch, BF, C2, HLA-A, B, C, DR, and GLO were determined. After decoding the samples the reliability of blind typing was found to be 84.4% according to segregation patters. Inconsistencies occurred mostly when A 4, A 2, or A 92 were present. The detection of silent A*Q0 and B*Q0 alleles was more critical than that of “difficult” allotypes. The quantitation of the C4A/B ratio by densitometry of stained gels or by conventional immunochemical measurements of serum C4 level could not substantially improve the identification of A*Q0 or B*Q0. C4 dependent activity in radial diffusion hemolysis showed satisfactory correspondence with the number of expressed C4B alleles. At least three haplotypes with two C4A genes (duplicated A genes) were observed as ascertained from offspring analysis in accordance with the MHC segregation pattern. Individuals with the duplicated C4A gene (C4A*3. A*2. in the absence of any other expressed A allele or together with C4A*92) showed only partial inhibition of Rodgers antisera. Partial inhibition of Chido antisera was seen in individuals with C4B 2 (in the absence of other B allotypes). The findings support the hypothesis of at least two structural C4 loci. The also demonstrate the inconsistency of quantitative data in the recognition of silent alleles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Alper CA (1976) Inherited structural polymorphism in human C2: Evidence for genetic linkage between C2 and Bf. J Exp Med 144: 1111–1115

    Google Scholar 

  • Alper CA, Awdeh ZL, Raum DD, Yunis EJ (1983) Hypothesis: Extended major histocompatibility complex haplotypes in man: Role of alleles analogous to murine t mutants. Clin Immunol Immunopathol 24:276–285

    Google Scholar 

  • Alper CA, Raum D, Karp S, Awdeh ZL, Yunis EJ (1983) Serum complement “supergenes” of the major histocompatibility complex in man (complotypes). Vox Sang 45:62–67

    Google Scholar 

  • Awdeh ZL, Alper CA (1980a) Inherited polymorphism of human C4 as revealed by desialization. Immunobiology 158:35–41

    Google Scholar 

  • Awdeh ZL, Alper CA (1980b) Inherited structural polymorphism of the fourth component of human complement (C4). Proc Natl Acad Sci USA 77:3576–3580

    Google Scholar 

  • Awdeh ZL, Raum D, Alper CA (1979) Genetic polymorphism of human complement C4 and detection of heterozygotes. Nature 282:205–207

    Google Scholar 

  • Awdeh ZL, Raum D, Yunis EJ, Alper CA (1983) Extended HLA complement allele haplotypes: Evidence for T/t-like complex in man. Proc Natl Acad Sci USA 80:259–263

    Google Scholar 

  • Bertrams J, Mauff G, Baur MP, Rittner C (1980) Association of rare gene products of the C2. C4, Bf gene cluster with type I diabetes. Immunobiology 157:203

    Google Scholar 

  • Bertrams J, Schoeps S, Schlicht V, Hintzen U, Luboldt W (1981) Der Polymorphismus der vierten Komplementkomponenten (C4) und seine Eignung für Vaterschaftsbegutachtung. Proc IX Int Congr Soc Forensic Hemogenetics. Bern 1981. pp 579–582

  • Borsos T, Rapp HJ (1965) Estimation of molecular size of complement components by Sephadex chromatography. J Immunol 94:510–513

    Google Scholar 

  • Bruun-Petersen G, Sorensen IJ, Buskjaer L, Lamm LU (1979) Genetic studies of complement C4 in man. Hum Genet 53:31–36

    Google Scholar 

  • Bruun-Petersen G, Lamm LU, Sørensen IJ, Buskjaer L, Mortensen JP (1981) Family studies of complement C4 and HLA in man. Hum Genet 59:260–267

    Google Scholar 

  • Fielder AHL, Walport MJ, Batchelor JR, Rynes RI, Black CM, Dodi IA, Hughes GRV (1983) Family study of the MHC in patients with SLE: importance of null alleles of C4A and C4B in determining disease susceptibility. Br Med J 286:425–428

    Google Scholar 

  • Fleischnick E, Raum D, Alosco SM, Gerald PS, Yunis E, Awdeh ZL, Granados J, Crigler JF Jr, Giles CM, Alper C (1983) Extended MHC haplotypes in 21-hydroxylase deficiency con-genital adrenal hyperplasia: Shared genotypes in unrelated patients. Lancet 1:152–156

    Google Scholar 

  • Giles CM (1980) Antigens in plasma. A seminar on antigens on blood cells and body fluids, p 3–49, Proc 33 Ann Meeting Am Ass Blood Banks, Washington DC, 1980

  • Greiner J, Weber FJ, Mauff G, Baur M (1980) Genetic polymorphisms of properdin factor B (Bf), the second component (C2), and the fourth component (C4) of complement in leprosy patients and healthy controls from Thailand. Immunobiology 158:134–138

    Google Scholar 

  • Kömpf J, Bissbort S (1975) Population genetics of red cell glyoxalase I (E.C.: 4.4.1.5). Gene frequencies in Southwestern Germany. Hum Genet 28:175–176

    Google Scholar 

  • Kurtz F, Juif JG, Hauptmann GR, Goetz J (1983) Insulin-dependent diabetes in children and fourth component of complement (C4). In: Chiumello G, Sperling M (eds) Recent progress in pediatric endocrinology, pp 351–358. Raven Press, New York

    Google Scholar 

  • Lamm LU, Buskjaer L, Petersen GB, Hauge M, Svejgaard A (1980) Complement C2 and C4 and factor B allotypes in insulin dependent diabetes (IDD) in Denmark. Abstract, VIIIth International Histocompatibility Conference, Los Angeles, 1980

  • Mancini G, Carbonara AO, Heremans JF (1965) Immunochemical quantitation of antigen by single radial immunodiffusion. Immunochemistry 2:235

    Google Scholar 

  • Martin A, Lachmann PJ, Halbwachs L, Hobart MJ (1976) Haemolytic diffusion plate assays for factors B and D of the alternative pathway of complement activation. Immunochemistry 13:317–324

    Google Scholar 

  • Mauff G, Hummel K, Pulverer G (1975) Properdin factor B (glycinerich beta-glycoprotein or C3 proactivator)-polymorphism: Genetic and biochemical aspects. First application to paternity cases. Z Immun Forsch 150:327–338

    Google Scholar 

  • Mauff G, Bender K, Mayerova A (1977) Untersuchungen zum Polymorphismus der vierten Komplementkomponente (C4). Proc VII Int Congr Soc Forensic Hemogenetics, pp 673–679, Hamburg 1977

  • Mauff G, Bender K, Fischer B (1978) Genetic polymorphism of the fourth component of human complement. Vox Sang 34:296–301

    Google Scholar 

  • Mauff G, Alper CA, Awdeh ZL, Batchelor JR, Bertrams J, Bruun-Petersen G, Dawkins RL, Démant P, Edwards J, Grosse-Wilde H, Hauptmann G, Klouda P, Lamm L, Mollenhauer E, Nerl C, Olaisen B, O'Neill G, Rittner C, Roos MH, Skanes V, Teisberg P, Wells L (1983a) Statement on the nomeclature of human C4 allotypes. Immunobiology 164:184–191

    Google Scholar 

  • Mauff G, Steuer M, Weck M, Bender K (1983b) The C4β-chain: Evidence for a genetically determined polymorphism. Hum Genet 64: 186–188

    Google Scholar 

  • Mickey MR, Terasaki PI (1980) Joint report: The serological data of the 8th workshop and summary analyses, pp 21–136. In: Terasaki PI (ed) Histocompatibility Testing 1980; UCLA Tissue Typing Laboratory, Los Angeles 1980

    Google Scholar 

  • Mollenhauer E, Schmidt R, Heinrichs M, Rittner C (1982) Progressive systemic sclerosis (scleroderma): Possible significance of silent alleles at the C4B locus. Abstract IV International Workshop Genetics of Complement, Boston 1982

  • Nordhagen R, Olaisen B, Teisberg P, Gedde-Dahl T Jr (1980) Association between the electrophoretically-determined C4M haplotype product and partial inhibition of anti-Cha. J Immunogenet 7:1–6

    Google Scholar 

  • Olaisen B, Teisberg P, Jonassen R, Gedde-Dahl T Jr (1979) The C4 system, formal and population genetics. Hum Genet 50: 187–192

    Google Scholar 

  • O'Neill GJ, Du Pont B (1979) Serum C4 levels. Chido, Rodgers, and allotypes of C4 component of complement. Transplant Proc 11:1102–1106

    Google Scholar 

  • O'Neill GJ, Du Pont B (1980) The genetic control of the fourth component of human complement C4. Immunobiology 158: 42–44

    Google Scholar 

  • O'Neill GJ, Yang SY, Tegoli J, Berger R, Du Pont B (1978a) Chido and Rodgers blood groups are distinct antigenic components of human complement C4. Nature 273:668–670

    Google Scholar 

  • O'Neill GJ, Yang SY, Du Pont B (1978b) Two HLA-linked loci controlling the fourth component of human complement. Proc Natl Acad Sci USA 75:5165–5169

    Google Scholar 

  • O'Neill GJ, Miniter P, Pollack MS, Du Pont B (1980) Different HLA antigen association for the functionally active and inactive products of the complement C4F1 allele. Fed Proc (Abstract) 39:685

    Google Scholar 

  • O'Neill GJ, Nerl CW, Kay PH, Christiansen FT, McCluskey J, Dawkins RL (1982) Complement C4 is a marker for adult rheumatoid arthritis. Lancet II:214

    Google Scholar 

  • Opferkuch W, Rapp HJ, Colten HR, Borsos T (1971) Immune hemolysis and the functional properties of the second (C2) and fourth (C4) component of complement. III. A comparison of rat C EDTA and guinea pig C EDTA in the titration of C2 and C4. J Immunol 106:927–931

    Google Scholar 

  • Porter RR (to be published) Complement polymorphism, the major histocompatibility complex and associated diseases: a speculation. Mol Biol Med l

  • Raum DD, Awdeh ZL, Glass D, Yunis E, Alper CA (1981) The location of C2, C4 and BF relative to HLA-B and HLA-D. Immunogenetics 12:473–483

    Google Scholar 

  • Ringelmann R, Opferkuch W, Röllinghoff M, Loos M (1969) Komplementmessungen mit Hilfe des Mikrolitersystems. Z Med Mikrobiol Immunol 154:329–343

    Google Scholar 

  • Rittner C, Mollenhauer E (1981) Zum Beweiswert der Komplementpolymorphismen C2, C4 und C6 in der Abstammungsbegut-achtung. Ärztl Lab 27:232–238

    Google Scholar 

  • Rittner C, Hauptmann G, Grosse-Wilde H, Grosshans F, Tongio MM, Mayer S (1975) Linkage between HLA (major histocom-batibility complex) and genes controlling the synthesis of the fourth component of complement. In: Kissmeyer-Nielsen F (ed) Histocompatibility testing, p 945. Copenhagen 1975

  • Rittner C, Zaschke S, Berghoff E, Mollenhauer E, Opferkuch W, Baur MP (1980) Comparative studies of human C4 phenotypes, their their population genetics, and association with HLA-B antigens. Immunobiology 158:119–128

    Google Scholar 

  • Rittner C, Tippett P, Giles CM, Mollenhauer E, Berger R, Nordhagen R, Buskjoer L, Petersen GB, Lamm L, Roos MH (to be published) An international reference typing for Ch and Rg determinants on rare human C4 allotypes. Vox Sang

  • Rood JJ van, van Leeuven A, Ploem JS (1976) Simultaneous detection of two cell populations by two-colour fluorescence and application to the recognition of B cell determinants. Nature 262:795–797

    Google Scholar 

  • Roos MH, Mollenhauer E, Démant P, Rittner C (1982) A molecular basis for the two locus model of human complement component C4. Nature 298:854–856

    Google Scholar 

  • Schröder R, Zander H, Andreas A, Mauff G (1983) Multiple sclerosis: Immunogenetic analyses of sib-pair double case families. II. Studies on the association of multiple sclerosis with C2, C4, BF, C3, C6, and GLO polymorphisms. Immunobiology 164:160–170

    Google Scholar 

  • Teisberg P, Olaisen B, Gedde-Dahl T Jr Thorsby E, Nordhagen R (1980a) Further investigations on the genetics of the C4 protein polymorphism. Immunobiology 158:45–49

    Google Scholar 

  • Teisberg P, Olaisen B, Nordhagen R, Thorsby E, Gedde-Dahl T Jr (1980b) A haemolytically non-active C4 gene product. Immunobiology 158:91–95

    Google Scholar 

  • Terasaki PI, Park MS (1976) Microdroplet lymphocyte cytotoxicity test. In: Ray JG, Hare DB, Pedersen DB, Mullally DI (eds) Manual of tissue typing techniques. DHEW publication No (NIH) 76-545, pp 69–80

Download references

Author information

Authors and Affiliations

  1. Hygiene-Institut der Universität Köln, Goldenfelsstr. 21, D-5000, Köln 41, Germany

    G. Mauff & Barbara Wachauf

  2. Institut für Humangenetik und Anthropologie der Universität Freiburg, Albertstr. 11, D-7800, Freiburg, Germany

    K. Bender

  3. Department of Immunology, Royal Postgraduate Medical School, University of London, Hammersmith Hospital, Ducane Road, W 12 OHS, London, UK

    Carolyn M. Giles

  4. Arbeitsbereich Transplantationsimmunologie, DRK-Blutspendezentrale Ulm und Abteilung für Transfusionsmedizin der Universität Ulm, Heidenheimer Str. 80, D-7900, Ulm, Germany

    S. Goldmann

  5. Lehrstuhl für Medizinische Mikrobiologie und Immunologie der Ruhr-Universität Bochum, Universitätsstr. 150, D-4630, Bochum, Germany

    W. Opferkuch

Authors
  1. G. Mauff
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K. Bender
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carolyn M. Giles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Goldmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Opferkuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barbara Wachauf
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mauff, G., Bender, K., Giles, C.M. et al. Human C4 polymorphism: Pedigree analysis of qualitative, quantiative, and functional parameters as a basis for phenotype interpretations. Hum Genet 65, 362–372 (1984). https://doi.org/10.1007/BF00291561

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00291561

Keywords

Search

Navigation