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Chido/Rodgers Blood Group System

CH/RG
Gene locus - C4A and C4B
Alleles

Introduction

The antigens for the Chido/Rogers (Ch/Rg) blood group system are the two isoforms C4A (acidic) and C4B (basic) of the 4th component 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 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.). Gene size is dependent on the presence or absence of the insert in intron 9 of C4B (see home page) and also on the outcome of the duplication process (Chung et al.).

The nucleotide and amino acid sequences of C4A and C4B isoforms show 99% identity except for a region, residues ~1000-1200, encoded by exons 25-28, in which 11 nucleotide substitutions resulting in eight amino acid differences. Diversity is created through reshuffling of these nucleotides in different alleles. The epitopes for Ch/Rg reside in this region and these amino acid changes define differences between the isotypes (C4A and C4B) and the allotypes (variant alleles). In particular four residues at position 1101-1106 define the two isotypes and four others specify the Rg and Ch epitiopes, as shown. Thus, the C4A isotype and the C4B isotypes are defined by the sequence spanning residues 1101-1106, PCPVLD and LSPVIH respectively; residues 1103, 1104 or PV being invariant in both proteins (Yu et al.). This area also defines the major Ch antigens Ch4 and Ch2. Residues 1157, 1188 and 1191 define the three Rg antigens as well as Ch 1, 3 and 6. Additonal alleles have been documented by sequencing of genomic DNA from four single short and long C4A or C4B molecules (acc. nos. M59816, U07856, M59815, , AF019413, AL049547, and U24578). 60 nucleotide variations were observed when comparing the four sequences in coding and non-coding regions. They are listed in Blanchong et al., Internat. Immunopharmacol., 1, 365, 2001; Table 3. Of the 19 nucleotide substitutions in the coding regions, five are silent substitutions, five are responsible for four amino acid differences between C4A and C4B and five others define the Rg and Ch blood groups; four others are private substitutions. We chose not to list these alleles since the uniqueness and incidence of each pattern of mutations is still not clear.

In the list of alleles, for alleles of C4A , the sequence with GenBank acc. no. K02403.1 is taken as reference; for alleles of C4B the reference has acc. no. NM_000592. Because of ambiguity concerning the sites of the first codons, the location of sites of nucleotide substitutions refers to numbers shown in the respective reference sequences.

Other database IDs and links

NCBI genes
720 for C4A
721 for C4B
Uniprot ID Genbank proteins
NP_009224 for C4A
NP_000583 for C4B
Gene nomenclature database ID
1323 for C4A
1324 for C4B
Genbank nucleic acids
NM_007293 for C4A
NM_000592 for C4B
NCBI homologenes for homologs and orthologs NCBI dbSNP for single nucleotide polymorphisms
720 for C4A
721 for C4B
OMIM ID - at Online Mendelian Inheritance in Man
120810 for C4A
120820 for C4B

Literature

Yu CY. Immunogenetics 27: 399, 1988, Teisberg et al., Ann. Hum. Genet. 52:77, 1988; Yu CY, The Journal of Immunology 146:1057, 1991, Daniels G. Blood Cell Biochemistry 6: 397,1995; Schenkel-Brunner H. Human Blood Groups, 2nd ed. Springer, NY, 2000, p.464, Blanchong et al. Internat. Immunopharmacol, 1, 365, 2001, Chung et al., Am. J. Hum. Genet. 71:823, 2002.

New PubMed entries with the terms Chido/Rodgers and blood from the last 30 days.
NCBI Book Sections with the terms Chido/Rodgers and blood.

Contributors

Joann M. Moulds, PhD, Life Share Blood Centers. Shreveport, Louisiana 71106; Marion E. Reid and Christine Lomas-Francis, Immunohematology, New York Blood Center, 310 East 67 St., New York, NY 10021;

Contributors for specific alleles are listed with the alleles.

Links


Updated 2011-11-13 22:46:38.147
 
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