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Polymorphism

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Description

Ch/Rg Gene locus - C4A and C4B

Introduction

The antigens for the Chido/Rogers (Ch/Rg) blood group system are the two isoforms C4A (acidic) and C4B (basic) of the 4th componnent of complement, part of the classical activation pathway. C4A and C4B are expressed as single chain precursors of 1744 residues (m.w. 200,000); post-translational proteolytic cleavage results in three polypeptide chains linked by disulfide bridges. Upon complement activation the protein is cleaved into several fragments, one of which, fragment C4d, contains the Ch/Rg epitopes. The proteolytic cleavages are incomplete reactions so many structural forms of C4 may be found in plasma. They are acquired from plasma by the erythrocyte. Following activation and cleavage fragment C4d remains attached to the erythrocyte membrane.

The two isoforms are glycosylated and contain three N-linked and one high-man units. Their nucleotide and amino acid sequences are nearly identical (99% identity) except for a region, residues ~1000-1200, encoded by exons 25-28, corresponding to fragment C4d, where eight amino acid differences occur. The epitopes for Ch/Rg reside in this region. and these amino acid changes define differences between the C4A and C4B and sequences of the variant alleles. In addition, the two proteins differ in hemolytic activity, and extent of binding to carbohydrate antigens and immune complexes of soluble antigens. In many cases the reaction with Chido- or Rodgers-specific antibodies may show selective association: Chido with C4B and Rodgers with C4A. However, as expected, a close relationship exists between the amino acid sequence within the polymorphic region and the respective phenotype although evidence suggests that Ch and Rg determinants may also be conformational epitopes, involving amino acid residues from different regions of the proteins.

The genes

They are the products of two closely linked and highly homologous genes, that reside within the Major Histocompatibility Complex (MHC) class III region on chromosome 6. Different haplotypes of this gene cluster exist such that one, two or three copies of the genes may exist in different individuals; some individuals may lack either C4A or C4B gene. Also, the C4B gene may exist in two forms, a short form (14.6 kb) or a long form (21 kb), the latter carrying a 6.4 kb endogenous HERV-K retrovirus in intron 9. Both C4A and the long form of C4B genes span 22 kb and contain 41 exons.

Function of proteins

C4A and C4B are components of the classical activation pathway of complement; they provide a surface for interaction between the antigen-antibody complex and other complement components.

Tissue distribution

Proteins are found in plasma and become adsorbed to blood cells, erythrocytes, macrophages. They are synthesized primarily by the liver with monocytes-macrophages, mammary gland, kidneys, the heart, thyroid gland, brain, testis, spleen.

Disease association

Inherited absence of genes of C4 may be a predisposing factor for diseases such as insulin-dependent diabetes and autoimmune chronic active hepatitis. Specific C4 allotypes or absence of genes have been associated with other autoimmune disorders including Grave's disease and rheumatoid arthritis. Low levels of C4 were found to be associated with autoimmune chronic active hapatitis. Lack of C4B results in increased susceptibility to bacterial meningitis in children. Lack of C4A results in a much greater susceptibility to systemic lupus erythromatosis. More generally, deficiency of C4 increases susceptibility to viral and bacterial infections and their severity.

About the alleles

The diversity of C4 complement system is extensive and it may play a functional role in modulating responses to infections and vulnerability to autoimmune diseases. The diversity may occur at different levels: gene size, gene number and levels of protein isotypes, as well as DNA variation. Copy number of C4A or C4B in different individuals may vary from none to two to six. Unequal homologous recombinations and gene conversions play a role in these duplications. Absence of genes is often caused by deletions of the gene cluster (Teisberg et al.; Schneider et al.).

Links

Attribution

  • This article is licensed under the GNU Free Documentation License. Sections excerpted from Blood Group Antigen Gene Mutation Database. See: Blumenfeld OO, Patnaik SK. Allelic genes of blood group antigens: a source of human mutations and cSNPs documented in the Blood Group Antigen Gene Mutation Database. Human Mutation. 2004 Jan; 23(1):8-16. PubMed ID: 14695527
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