C Genes of Immunoglobulins 

C genes encode for the constant (C) regions of immunoglobulin (Ig) heavy and light chains and therefore define the isotypes of H (g, m, a, d and l) and L (k, l) chains. The simplest structure is that of the Ck gene, which is unique in both the human and mouse species. It encodes for the entire constant region of the k chain. In humans, the Ck gene has three allelic variants based on single amino acid substitutions at two positions, which constitute the Km allotypes. The Ck gene is separated from the Jk region by a noncoding region of 1.2 kbp that contains a k enhancer. A second enhancer region is present in the 3′ flanking region. The organization of the Cl genes is somewhat more complicated, and there are some minor differences between humans and mouse. In both cases, they are present as tandem duplications of a JlCl unit, in which each J gene is separated from the C gene by a noncoding sequence of about 1 kbp. There are four discrete tandems in the mouse, Jl1Cl1 to Jl4Cl4, of which only three are functional. In humans, four functional tandem JC pairs are present, in addition to three pairs of pseudogenes. An enhancer region is present 3′ of the coding region in both species. In humans, the IgK and IgL loci are located at chromosomal positions 2p12 and 22q11, respectively.

 The heavy-chain constant gene locus, located at 14q32 in humans, spans over 200 kbp. The detailed organization of the individual human CH genes is given in Figure 1. Some characteristic features may be identified. First, each isotype is encoded by a mosaic of exons that precisely reflects the domain structure of the Ig. The constant region of Cm is encoded by four exons, Cm1 to Cm4, corresponding to the four constant domains of the m chain, whereas in the case of the Cg isotypes one of the exons encodes the hinge region. Second, each isotype encoding C gene has additional membrane exons (one or two, depending on the isotype) that encode the transmembrane section and the short COOH-terminal cytoplasmic tail. Coding units that make secreted or membrane heavy chains result from alternative splicing and terminate at two distinct polyadenylation sites (see Fig. 1). The overall CH region also contains two pseudogenes. It will be noticed that a switch region is located at 5′ of each set of C genes, with the exception of the d locus, which accounts for the coexpression of IgM and IgD at the surface of mature B cells. 

Figure 1. Organization of human heavy-chain constant region genes. Exons encoding discrete constant domains (CH,( hinge regions (H), or transmembrane portion of surface heavy chains (M) are represented by open squares or rectangles. Polyadenylation sites are indicated by a dot. (From Ref. 1, with permission; adapted from Ref. 2.)

A final remark should be made regarding the general organization of the regulating elements that control IgH gene expression. Promoter regions are present at 5′ of each V gene and will be discussed elsewhere. Enhancers are split into two regions; one is located at 5′ of the Sm switch region, so that with each switching event it will control the newly adjacent isotype gene; the other is located at 3′ of the entire IgCH locus and may thus control whatever gene is to be turned on.

References

1. J.-P. Revillard (1998) In Immunologie, De Boeck Université, Paris-Bruxelles, p. 57. 

2. J. D. Capra and J. D. Duker (1989) J. Biol. Chem. 264, 12745.