The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene.

The human complement component C4A and C4B genes are located within the class III region of the MHC. The polymorphic C4 genes are highly complex including variations in class (isotype), size, and number of genes. The DNA sequence for a C4A gene has been determined, except for a large intron of 6 to 7 kb long. The C4A gene consists of 41 exons encoding a transcript for a precursor protein of 1744 amino acid residues. Several structural and functional aspects of C4 have been located to individual exons. The active site of the anaphylatoxin C4a matches to a splice junction. Some unique properties of C4, such as, the alpha-gamma-chain junction, the tyrosine sulfation sites, and the post-secretory metalloprotease cleavage site, are encoded by a single exon. Comparison of human C4 with published data for mouse C4, human C3 and rat alpha 2 macroglobulin genes revealed that these evolutionary-related genes share very similar exon-intron structures. Altogether 20 polymorphic sites in human C4 have been detected by various techniques. Presumably, these polymorphic residues account for the functional, structural, and serologic variations observed among the various allotypes. A PvuII restriction length polymorphism has been detected within the region of DNA coding for C4a. The intergenic region between C4 and the neighboring 21-hydroxylase gene, CYP21, is approximately 3028 bp in size.