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PMID: 12226794 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex.

American journal of human genetics ·Vol. 71 ·No. 4 ·2002-10-00 ·Pages 823-37

Chung EK, Yang Y, Rennebohm RM, Lokki ML, Higgins GC, Jones KN, Zhou B, Blanchong CA, Yu CY

Abstract

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. We applied definitive techniques to elucidate (a) the complement C4 polymorphisms in gene sizes, gene numbers, and protein isotypes and (b) their gene orders. Several intriguing features are unraveled, including (1) a trimodular RCCX haplotype with three long C4 genes expressing C4A protein only, (2) two trimodular haplotypes with two long (L) and one short (S) C4 genes organized in LSL configurations, (3) a quadrimodular haplotype with four C4 genes organized in a SLSL configuration, and (4) another quadrimodular structure, with four long C4 genes (LLLL), that has the human leukocyte antigen haplotype that is identical to ancestral haplotype 7.2 in the Japanese population. Long-range PCR and PshAI-RFLP analyses conclusively revealed that the short genes from the LSL and SLSL haplotypes are C4A. In four informative families, an astonishingly complex pattern of genetic diversity for RCCX haplotypes with one, two, three and four C4 genes is demonstrated; each C4 gene may be long or short, encoding a C4A or C4B protein. Such diversity may be related to different intrinsic strengths among humans to defend against infections and susceptibilities to autoimmune diseases.

MeSH Terms
Arthritis, Juvenile/genetics Complement C4a/genetics Complement C4b/genetics Gene Dosage HLA Antigens Haplotypes Humans Lupus Vulgaris/genetics Major Histocompatibility Complex/genetics Molecular Sequence Data
Chemicals
HLA Antigens Complement C4a Complement C4b
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Chung Erwin K
Children's Research Institute, Columbus, OH 43205, USA.
Yang Yan
Rennebohm Robert M
Lokki Marja-Liisa
Higgins Gloria C
Jones Karla N
Zhou Bi
Blanchong Carol A
Yu C Yung
References (42)
42 references, click to expand
  1. The C4 system: quantitative studies of different genotypes.
    Immunobiology. 1980;158(1-2):82-5 PMID: 6782011
  2. An unequal crossover between the RCCX modules of the human MHC leading to the presence of a CYP21B gene and a tenascin TNXB/TNXA-RP2 recombinant between C4A and C4B genes in a patient with juvenile rheumatoid arthritis.
    Exp Clin Immunogenet. 1999;16(2):81-97 PMID: 10343159
  3. The 1982 revised criteria for the classification of systemic lupus erythematosus.
    Arthritis Rheum. 1982 Nov;25(11):1271-7 PMID: 7138600
  4. A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B.
    Nature. 1984 Jan 19-25;307(5948):237-41 PMID: 6559257
  5. Human C4 haplotypes with duplicated C4A or C4B.
    Am J Hum Genet. 1984 Jan;36(1):72-9 PMID: 6607672
  6. Genetics of human C4 polymorphism: detection and segregation of rare and duplicated haplotypes.
    Immunogenetics. 1984;19(4):321-33 PMID: 6201442
  7. Complement polymorphism, the major histocompatibility complex and associated diseases: a speculation.
    Mol Biol Med. 1983 Jul;1(1):161-8 PMID: 6679872
  8. Polymorphism of human complement component C4.
    Immunogenetics. 1985;21(2):173-80 PMID: 3838531
  9. Molecular genetics of the fourth component of human complement and steroid 21-hydroxylase.
    Immunol Rev. 1985 Oct;87:39-60 PMID: 2997023
  10. Haplotype study on C4 polymorphism in Japanese. Associations with MHC alleles, complotypes, and HLA-complement haplotypes.
    Immunogenetics. 1985;22(4):359-65 PMID: 3850846
  11. C4 phenotypic variation suggests an unusual class III gene organization.
    Vox Sang. 1985;48(2):110-5 PMID: 3878038
  12. Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium.
    Nature. 1999 Oct 28;401(6756):921-3 PMID: 10553908
  13. Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity.
    EMBO J. 1986 Nov;5(11):2873-81 PMID: 2431902
  14. Phenotyping of human complement component C4, a class-III HLA antigen.
    Biochem J. 1986 Nov 1;239(3):763-7 PMID: 3103606
  15. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
    Endocr Rev. 2000 Jun;21(3):245-91 PMID: 10857554
  16. 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.
    J Exp Med. 2000 Jun 19;191(12):2183-96 PMID: 10859342
  17. The endogenous retroviral insertion in the human complement C4 gene modulates the expression of homologous genes by antisense inhibition.
    Immunogenetics. 2001 Feb;53(1):1-9 PMID: 11261924
  18. Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4.
    Int Immunopharmacol. 2001 Mar;1(3):365-92 PMID: 11367523
  19. Genetics of human complement component C4 and evolution the central MHC.
    Front Biosci. 2001 Aug 1;6:D904-13 PMID: 11487475
  20. Genetic organization of the human MHC class III region.
    Front Biosci. 2001 Aug 1;6:D914-26 PMID: 11487476
  21. Characterization of a de novo conversion in human complement C4 gene producing a C4B5-like protein.
    J Immunol. 2002 Jun 1;168(11):5652-8 PMID: 12023363
  22. The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes.
    J Immunol. 2002 Aug 1;169(3):1570-8 PMID: 12133986
  23. Determining the one, two, three, or four long and short loci of human complement C4 in a major histocompatibility complex haplotype encoding C4A or C4B proteins.
    Am J Hum Genet. 2002 Oct;71(4):810-22 PMID: 12224044
  24. Structural polymorphism of the fourth component of human complement.
    J Clin Invest. 1969 Dec;48(12):2283-92 PMID: 5389795
  25. Genetic polymorphism of C4 in man and localisation of a structural C4 locus to the HLA gene complex of chromosome 6.
    Nature. 1976 Nov 18;264(5583):253-4 PMID: 1088823
  26. Two HLA-linked loci controlling the fourth component of human complement.
    Proc Natl Acad Sci U S A. 1978 Oct;75(10):5165-9 PMID: 368809
  27. Genetic polymorphism of human complement C4 and detection of heterozygotes.
    Nature. 1979 Nov 8;282(5735):205-7 PMID: 492334
  28. Inherited structural polymorphism of the fourth component of human complement.
    Proc Natl Acad Sci U S A. 1980 Jun;77(6):3576-80 PMID: 6932037
  29. The study of a French family with two duplicated C4A haplotypes.
    Hum Genet. 1987 Dec;77(4):359-65 PMID: 2891605
  30. A structural model for the location of the Rodgers and the Chido antigenic determinants and their correlation with the human complement component C4A/C4B isotypes.
    Immunogenetics. 1988;27(6):399-405 PMID: 2453459
  31. Restriction fragment length polymorphisms of the complement component C4 loci on chromosome 6: studies with emphasis on the determination of gene number.
    Ann Hum Genet. 1988 May;52(Pt 2):77-84 PMID: 2907852
  32. Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 gene repeats in 21-hydroxylase deficiency haplotypes.
    EMBO J. 1989 May;8(5):1393-402 PMID: 2788573
  33. Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A.
    Proc Natl Acad Sci U S A. 1990 Sep;87(17):6868-72 PMID: 2395880
  34. A novel immunoassay for the quantitation of human C4 gene products.
    Complement Inflamm. 1990;7(2):95-101 PMID: 2225796
  35. The genomic structure of two ancestral haplotypes carrying C4A duplications.
    Immunogenetics. 1991;34(4):247-51 PMID: 1680806
  36. Quantitation of the human component C4: definition of C4 Q0 alleles and C4A duplications.
    Vox Sang. 1992;62(2):117-23 PMID: 1519366
  37. The dichotomous size variation of human complement C4 genes is mediated by a novel family of endogenous retroviruses, which also establishes species-specific genomic patterns among Old World primates.
    Immunogenetics. 1994;40(6):425-36 PMID: 7545960
  38. The reaction mechanism of the internal thioester in the human complement component C4.
    Nature. 1996 Jan 11;379(6561):177-9 PMID: 8538770
  39. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus.
    Arthritis Rheum. 1997 Sep;40(9):1725 PMID: 9324032
  40. Reference typing report for complement component C4.
    Exp Clin Immunogenet. 1998;15(4):249-60 PMID: 10072635
  41. 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.
    J Biol Chem. 1999 Apr 23;274(17):12147-56 PMID: 10207042
  42. A molecular basis for the two locus model of human complement component C4.
    Nature. 1982 Aug 26;298(5877):854-6 PMID: 6180321
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/342777
Published
2002-10-00
Epub
2002-00-11
Pages
823-37
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC378539
Subset
IM
Grants
NIDDK NIH HHS · P01 DK055546 · United States
NIAMS NIH HHS · R01 AR43969 · United States
NIDDK NIH HHS · P01 DK55546 · United States
NCRR NIH HHS · 1P41 RR06009 · United States
NCRR NIH HHS · P41 RR006009 · United States
Databases
GENBANK
AF019413, AL049547, L26260, L26261, L26262, L26263, M12792, M12793, M13935, M13936, M26856, M26857, M58915, M59816, U07856, U24488, U24578, U89337
OMIM
120810, 120820, 152700, 201910, 600985, 604977
External Links
PubMed source DOI: 10.1086/342777 PMC Full Text View journal details
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